Roflumilast Formulations with an Improved Pharmacokinetic Profile

ABSTRACT

An improved a method of treating a patient having a disorder responsive to PDE-4 inhibition by administering roflumilast. The improvement involves administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of a PDE4-inhibiting amount of roflumilast. Such disorders include inflammatory disorders such as inflammatory dermatoses, including psoriasis, atopic dermatitis and seborrheic dermatitis. Such disorders also include inflammatory diseases in a variety of organs, especially the lungs (asthma, COPD). Because of reduced side effects with topical administration due to the improved pharmacokinetics (PK) characteristics, it may be possible to provide higher systemic exposures (AUCs) with topical administration, resulting in greater therapeutic efficacy than with the oral route of administration.

This application is a continuation in part of U.S. Ser. No. 17/155,679filed Feb. 5, 2021, which is a continuation in part of U.S. Ser. No.17/102,056 filed Nov. 23, 2020, which is a continuation of U.S. Ser. No.16/136,804 filed Sep. 20, 2018, which issued as U.S. Pat. No. 10,940,142issued on Mar. 9 2021, which is a continuation of U.S. Ser. No.15/848,505 filed Dec. 20, 2017, which issued as U.S. Pat. No. 10,105,354issued on Oct. 23, 2018, which is a continuation of U.S. Ser. No.15/676,356 filed Aug. 14, 2017, which issued as U.S. Pat. No. 9,884,050issued on Feb. 6, 2018, which is a divisional of U.S. Ser. No.15/616,409 filed Jun. 7, 2017, which issued as U.S. Pat. No. 9,895,359,issued Feb. 20, 2018, the disclosures of which are incorporated hereinin their entirety by reference.

FIELD OF THE INVENTION

The invention pertains to methods for treating a patient having adisorder that is responsive to treatment with PDE-4 inhibition by thetopical administration of a roflumilast formulation having a roflumilastrelease profile that produces in the patient a flattened plasmaconcentration time curve and a reduced Cmax relative to administrationof an equivalent amount of roflumilast in an oral composition. Themethods of treatment of this invention provide a sufficiently high areaunder the plasma-roflumilast concentration curve (AUC) to attain asystemically effective level of roflumilast without rapid-onset peakplasma concentration (Cmax) (i.e., short Tmax). It has been discoveredthat these pharmacokinetic characteristics result in a reduction ofundesirable side effects associated with oral roflumilast therapy.

BACKGROUND OF INVENTION

Roflumilast is known to be suitable as a bronchial therapeutic agent aswell as for the treatment of inflammatory disorders. Compositionscontaining roflumilast are used in human and veterinary medicine andhave been proposed for the treatment and prophylaxis of diseasesincluding but not limited to: inflammatory and allergen-induced airwaydisorders (e.g. bronchitis, asthma, COPD); dermatoses (e.g.proliferative, inflammatory and allergen-induced skin disordersincluding psoriasis, seborrheic dermatitis, and atopic dermatitis), andgeneralized inflammations in the gastrointestinal region (Crohn'sdisease and ulcerative colitis). Currently, roflumilast is approved forsystemic administration (oral) to treat inflammatory disorders involvingthe lungs, such as chronic obstructive pulmonary disease (COPD).

Roflumilast and its synthesis were described in U.S. Pat. No. 5,712,298(the “'298 patent”), incorporated herein by reference.* It has long beenrecognized that pharmaceutical compounds having phosphodiesterase(PDE)-inhibiting properties, such as roflumilast, are useful fortreating inflammatory disorders, including inflammatory dermatoses, suchas psoriasis and atopic dermatitis ('298 patent, col 11 lines 52-61) andother chronic inflammatory and allergen-induced dermatoses. Fortreatment of such dermatoses, roflumilast emulsions, suspensions, gelsor solutions for topical application have been described ('298 patent,col 12, lines 37-64). Although oral tablets of roflumilast have beencommercialized, the low aqueous solubility of the compound has beenreported to be only 0.53 mg/l at 21° C. in WO95/01338 (corresponding tothe '298 patent and incorporated herein by reference in its entirety).This low aqueous solubility has been problematic for the development ofparenteral preparations and topical emulsions, suspensions, gels orsolutions containing water. In U.S. Pat. No. 9,205,044 (incorporatedherein by reference), the poor water solubility of roflumilast wasovercome by using an alkoxylated fat, specifically polyoxyethylated12-hydroxystearic acid, as a co-solvent for parenteral administration.In EP 1511516B1 (corresponding to published U.S. application Ser. No.14/075,035 incorporated herein by reference), the low water solubilityof roflumilast was overcome in topical emulsion (cream) formulations byformulating with polyethylene glycol 400 (PEG 400) in concentrationsover 62% (w/w) while keeping water weight percentages under 10%. *Unless otherwise indicated, references incorporated herein by referenceare incorporated in their entireties for all purposes.

Topical application of potent pharmacological agents like roflumilastfor treating skin diseases has been found to provide superior delivery,lower systemic exposure and greater ease of use for patients. Themolecular structure of the compound ultimately dictates the ability ofthe drug to cross the epithelium of the tissue to which the product isapplied. For topical application to skin, selection of the components ofthe formulation dictates the maximum skin permeation that the formulatorcan achieve. Creams, lotions, gels, ointments and foams are just a fewof the more familiar forms of topical products that contain activepharmaceutical ingredients (API) for application to the skin. To assureconsistent delivery of the API into or across the skin, it must remaineither: 1) dissolved over the shelf life of the topical product, or 2)suspended as particles having unchanged crystal habit and unchangedparticle size distribution over the shelf life of the topical product.

The ability of a dissolved active ingredient to permeate the barrier ofthe skin is determined by its molecular structure. A well -knownrelationship between molecular structure and skin penetration is thatincreasing molecular weight decreases the rate that an active crossesthe skin (J D Bos, M M Meinardi, Exp Dermatol. 2000 June; 9(3):165-9).Another well-understood relationship is that increasing theoctanol-water partition coefficient of a hydrophilic active initiallyincreases the rate that an active permeates the skin, but then decreasesskin permeation once the active becomes too lipophilic to partition outof the stratum corneum and into the lower layers of the epidermis (D. W.Osborne and W. J. Lambert, Prodrugs for Dermal Delivery, K. B. Sloaneed., Marcel Dekker, New York 163-178 (1992)). The optimal octanol-waterpartition coefficient is usually at log P values of 2-3. The rate thatan active ingredient crosses into the viable epidermis can be furthermodified based on the composition of the topical product. Final pH ofthe formulation may be critical, because dissolved ionized activeingredients typically do not permeate the skin as effectively as activeingredients that do not carry a charge (N. Li, X. Wu, W. Jia, M. C.Zhang, F. Tan, and J Zhang. Drug Dev Indust Pharm 38(8)985-994).Functional ingredients such as skin penetration enhancers (D. W. Osborneand J. J. Henke, Pharmaceutical Technology 21(11)58-66(1997)) can beadded to the topical product to increase skin permeation. For adissolved active in the topical product, the closer the drugconcentration is to the amount of active required to saturate the drugproduct, the greater the thermodynamic driving force of the active tocross the skin, i.e. the greater the skin flux of the active. Thescientific literature guides formulators on how to increase penetrationthrough the polar route, the nonpolar route, and the intercellular lipidpathway or transfollicular penetration. While these theories andmechanisms are sometimes conflicting, it is generally accepted that themost consistent skin permeation of a drug from a topical product occurswhen the active ingredient is dissolved in the formulation. For thisreason, formulators generally avoid developing a topical product thatwill have particles or crystals of the active ingredient precipitateduring storage according to labeled storage instructions. Precipitationof the active ingredient can occur for various reasons. Particularactive ingredients, when formulated with particular pharmaceuticalexcipients will tend to form supersaturated solutions. At the time ofmanufacture, all of the active ingredient will be in solution. Afterdays, weeks, or months, this metastable topical product will equilibrateand active ingredient particles will form. If a topical product containsa volatile solvent such as ethanol, then evaporation of the solvent uponstorage could result in precipitation of the active ingredient. A lesssoluble polymorph (Pudipeddi and Serajuddin, J. Pharm. Sci., 94(5)929-939 (2005)) may nucleate in the topical product and form activeingredient particles that will not re-dissolve. Other products may beformulated too close to the saturation limit of the active ingredientwith the result that minor shifts in storage temperatures will causeprecipitation. It should be noted that the dramatic temperature shiftsthat can occur during shipping are expected to cause the reversibleprecipitation of the active ingredient. Regardless of the reason,irreversible precipitation of the active ingredient during storage of atopical product can have profound effects on the bioavailability andefficacy of a topical product, because only dissolved active ingredientscan penetrate into intact stratum corneum, the outermost layer ofepithelium of the skin.

For a suspended active ingredient, properties in addition to molecularstructure influence skin permeation. The ratio of dissolved to suspendedactive ingredient can have a significant influence on the amount ofactive delivered after topical application. It has been shown thatoptimal drug delivery can be achieved for particular drugs andparticular diseases by utilizing a topical composition that includes adissolved active ingredient that has the capacity to permeate thestratum corneum layer of the epidermis and become availablesystemically, along with an active ingredient in a microparticulatestate that does not readily cross the stratum corneum of the epidermis(U.S. Pat. No. 5,863,560 hereby incorporated by reference). Anotherproperty of a suspended active ingredient that affects its delivery isthe distribution of suspended particle size. It has been shown that a 6micron particle will target the hair follicle and penetrate to a depthof 500 micrometers in a terminal hair. For a suspended particle of 0.75microns to 1.5 microns in size, the particle penetrates the terminalhair shaft to a depth of 800 micrometers (A Patzelt, F Knorr, UBlume-Peytavi, W Sterry, J Lademann, Drug Discovery Today: DiseaseMechanisms, 5(2)2008 pages e173-e181). Thus, for suspended activeingredients, skin permeability depends on the following properties: 1)molecular structure of dissolved active ingredient, 2)particulate/crystalline structure of the suspended active ingredient, 3)particle size of the suspended active ingredient, and 4) particle sizedistribution of the suspended active ingredient. The ability of atopical product composition to modify the skin permeation is similar forsuspended active ingredients and dissolved active ingredients. Becauseskin permeability is dependent on additional properties of the suspendedactive ingredients, consistent delivery from topical products containingsuspended actives is more difficult to maintain than for topicalproducts containing only dissolved active ingredients.

Consistent delivery of a suspended active ingredient from a topicalproduct is assured by formulation into a product in which the suspendedparticles do not significantly change in size or amount over the shelflife of the product. Change over time in the ratio of dissolved activeingredient to particulate active ingredient can dramatically change theskin permeation of the active ingredient. The same mechanisms describedabove (supersaturation, temperature changes, evaporation, polymorphictransformation) that can cause precipitation of dissolved activeingredients can alter the dissolved-to-particulate ratio for suspendedactive ingredients. Change over time in the particle size or particlesize distribution of the dispersed active ingredient can alsodramatically change the skin permeation of the active ingredient.Sometimes this change in particle size or particle size distribution canbe explained by Ostwald ripening of the particles. Ostwald ripeningoccurs when small particles in the topical product dissolve andredeposit onto larger particles suspended in the same container oftopical product. Over time this phenomenon shifts the particle sizedistribution toward larger particles at the expense of the smallerparticles. Ostwald ripening and precipitation of a less solublepolymorph are two major problems in developing topical productscontaining suspended actives.

In addition to crystal growth and changes in particle size which candramatically change the skin permeation of roflumilast, successfultreatment can be also affected by side effects which can lead totreatment discontinuation. The prescribing information pertaining toDALIRESP® (oral roflumilast tablets marketed in the U.S.) warns ofpsychiatric adverse reactions (insomnia, anxiety, depression, suicidalideation and suicidal behavior), weight loss and gastrointestinal sideeffects when patients are treated with 500 mcg once daily. Because ofthe high incidence of gastrointestinal side effects, including severenausea and diarrhea, the prescribing information pertaining to DALIRESP®instructs that it may be beneficial to take half of the therapeuticallyeffective dose, 250 mcg, once daily for 4 weeks prior to commencing thetherapeutically effective dose of 500 mcg per day so as to reduce therate of treatment discontinuation. The prescribing information forDAXAS® (oral roflumilast tablets marketed outside the U.S.) does notinstruct the patient to take a reduced non-therapeutically effectivedosage prior to taking the therapeutic dose. However, the prescribinginformation for DAXAS® does report a high incidence of diarrhea, nausea,and abdominal pain associated with this medication.

When roflumilast is orally administered, the drug is rapidly absorbed,resulting in a sharp spike in plasma concentration. According todocuments filed in the FDA, upon initial administration of a roflumilasttablet, a Cmax (peak plasma concentration) of 7.34 mcg/l that spiked ata Tmax (time after administration to reach Cmax) 1 hour afteradministration occurred with a 500 mcg tablet and a Cmax of 3.99 mcg/lthat spiked at a Tmax of 1 hour occurred with a 250 mcg tablet. Thespike in Cmax followed a clear dose-response relationship. A similardose-response relationship was shown for the occurrence ofgastrointestinal side effects, suggesting a possibility that these sideeffects are associated with the spike in Cmax.

When multiple doses of oral roflumilast are administered, exposurefollows a “peak to trough” pattern. This pattern results in an episodicvariation in blood levels of drug and continued gastrointestinal sideeffects.

Bolle, U.S. Patent Application Publication No. 2006/0084684 disclosestopical formulations of roflumilast, salts of roflumilast, the N-oxideof roflumilast, and salts of the N-oxide. Bolle discloses that suchformulations are useful to apply to skin lesions for the local treatmentof skin disorders or to administer topically for the systemic treatmentof skin disorders and other disorders, such as COPD. Bolle disclosesthat the systemic effect of topical application of the roflumilastformulations is comparable to that of an oral dosage form. Bolle furtherdiscloses, in paragraph 0080 that “Comparison with oral administrationshows that, irrespective of the composition of the topical preparation,similar Cmax and AUCs and similar excretions with the urine areachieved.”

Although Bolle does not discuss the incidence of side effects that occurfollowing topical administration of the roflumilast formulations,because Cmax with the topical formulations, irrespective of thecomposition of the topical formulation, is similar to that which isobtained with orally administered formulations, and because side effectsare correlated with Cmax and Tmax, it would be expected thatadministration of the topical formulations of Bolle would cause anincidence of side effects similar to that caused by orally administeredformulations.

Although oral tablets of roflumilast have been commercialized, topicaland parenteral administration require different formulations due to thelow aqueous solubility of the compound which has been reported to beonly 0.53 mg/l at 21° C. in WO95/01338 (corresponding to the '298 patentand incorporated herein by reference). This low aqueous solubility hasbeen problematic for the development of parenteral preparations andtopical emulsions, suspensions, gels or solutions containing water. InU.S. Pat. No. 9,205,044 (incorporated herein by reference), the poorwater solubility of roflumilast was overcome by using an alkoxylatedfat, specifically polyoxyethylated 12-hydroxystearic acid, as aco-solvent for parenteral administration. In EP 1511516B1 (correspondingto published U.S. application Ser. No. 14/075,035 incorporated herein byreference), the low water solubility of roflumilast was overcome intopical emulsion (cream) formulations by formulating with polyethyleneglycol 400 (PEG 400) in concentrations over 62% (w/w) while keepingwater weight percentages under 10%.

Topical application of potent pharmacological agents like roflumilasthas been found to provide superior delivery and greater ease of use forpatients. The molecular structure of the compound ultimately dictatesthe ability of the drug to cross the epithelium of the tissue to whichthe product is applied. For topical application to skin, selection ofthe components of the formulation dictates the maximum skin permeationthat the formulator can achieve. Creams, lotions, gels, ointments andfoams are just a few of the more familiar forms of topical products thatcontain active pharmaceutical ingredients (API) for application to theskin.

A need exists for a method of treating patients having PDE-4 inhibitorresponsive disorders with roflumilast, that results in a therapeuticallyeffective systemic dose, does not result in a spike in Cmax, while stillproviding a high AUC, and which, therefore, is pharmaceuticallyefficacious but is associated with a decreased incidence of sideeffects. Indeed, the absence or reduced side effects allow fortherapeutic doses to be administered that provide higher systemicexposures (AUCs) than are possible orally and with greater diseaseefficacy.

SUMMARY OF THE INVENTION

In accordance with the present invention, an improved method of treatinga patient having a disorder responsive to PDE-4 inhibition byadministering a PDE-4-inhibiting amount of roflumilast, involvesadministering the roflumilast topically in a composition having aroflumilast release profile that produces in the patient a flattenedplasma concentration time curve and a reduced Cmax relative to oraladministration of a PDE4-inhibiting amount of roflumilast. Suchdisorders include inflammatory disorders such as inflammatorydermatoses, including psoriasis, atopic dermatitis and seborrheicdermatitis. As used herein, a disorder is responsive to PDE-4 inhibitionif such inhibition results in a prevention of the disorder or adiminution of its severity, duration or recurrence, such disorders alsoinclude inflammatory diseases in a variety of organs, especially thelungs (asthma, COPD). Because of reduced side effects with topicaladministration due to the above-described pharmacokinetics (PK)findings, it may be possible to provide higher systemic exposures (AUCs)with topical administration, resulting in greater therapeutic efficacythan with the oral route of administration.

In a preferred embodiment, the topically applied composition containsfrom about 0.1% w/w to about 0.5% w/w roflumilast. In a preferredembodiment, the topically applied composition is in the form of a creamor a foam.

In a preferred embodiment, the composition has a roflumilast releaseprofile that results in a reduced Cmax, longer Tmax and flattened plasmaconcentration time curve relative to that achieved with oraladministration of an effective amount of roflumilast in an oralcomposition marketed under the trademarks DALIRESP® and DAXAS®.

It has been discovered that topical roflumilast compositions having theabove-described PK properties produce reduced gastrointestinal,psychiatric, and weight loss side effects as compared to prior artorally administered compositions.

Thus, in another embodiment, the present invention provides a method oftreating a patient suffering from a disorder that can be treated byPDE-4 inhibition that comprises: administering a topical pharmaceuticalcomposition comprising 0.5% w/w of roflumilast and a pharmaceuticallyacceptable carrier, wherein administration of said composition resultsin reduced gastrointestinal and other side effects relative to oraladministration of roflumilast in a composition of roflumilast marketedunder the trademark DALIRESP® or DAXAS®.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows Sample 19-2 “dry” roflumilast crystals fromferrer-Interquim S.A. Batch A14367P, the drug substance used in all theexamples in this specification. The roflumilast crystals are 0.01mm-0.02 mm in length.

FIG. 2 shows Sample 20-3 roflumilast crystals suspended in equimolarhexylene glycol:water solution after storage for six weeks at roomtemperature under 10× power. The roflumilast crystals are 0.01 mm-0.02mm in length.

FIG. 3 shows Sample 20-2 roflumilast crystals suspended in equimolardiethylene glycol monoethyl ether:water solution after storage for sixweeks at room temperature. The roflumilast crystals are 0.04 mm-0.20 mmin length and 0.01 mm-0.02 mm in width.

FIG. 4 shows Sample 20-3 roflumilast crystals suspended in equimolarhexylene glycol:water solution after storage for six weeks at roomtemperature under 4× power. The roflumilast crystals are 0.01 mm-0.02 mmin length.

FIG. 5 shows Sample 21-2 roflumilast crystals suspended in equimolarethanol:water solution after storage for six weeks at room temperature.The roflumilast crystals are 0.05 mm-0.25 mm in length and 0.02 mm inwidth.

FIG. 6 shows Sample 21-3 roflumilast crystals suspended in equimolar PEG400:water solution after storage for six weeks at room temperature. Theroflumilast crystals are 0.05 mm-0.07 mm in length and 0.02 mm in width.

FIG. 7 shows Sample 21-4 roflumilast crystals suspended in equimolarDMSO:water solution after storage for six weeks at room temperature. Theroflumilast crystals are 0.10 mm-0.67 mm in length and 0.02 mm-0.10 mmin width.

FIG. 8 shows Sample 21-5 roflumilast crystals suspended in equimolarpropylene glycol:water solution after storage for six weeks at roomtemperature. The roflumilast crystals are 0.20 mm-1.60 mm in length and0.02 mm in width.

FIG. 9 shows Sample 20-1 roflumilast crystals suspended in equimolarNMP:water solution after storage for six weeks at room temperature. Theroflumilast crystals are 0.10 mm-1.55 mm in length and 0.02 mm-0.13 mmin width.

FIG. 10 shows Sample 21-1 roflumilast crystals suspended in HG:NMP:Water(water mole fraction=1.2) solution after storage for six weeks at roomtemperature. The roflumilast crystals are 0.02 mm-0.04 mm in length and0.02 mm in width.

FIGS. 11A and 11B show roflumilast particles precipitated in a creamcomposition after one freeze thaw cycle. FIG. 11 a shows Sample 36-1roflumilast particles precipitated in a cream composition withdiethylene glycol monoethyl ether (DEGEE) and without hexylene glycol.The three largest roflumilast particles were measured (0.07 mm×0.09 mm;0.06 mm×0.06 mm; and 0.10 mm×0.05 mm) and found to have a mean surfacearea of 5,000 square microns. FIG. 11 b shows Sample 36-2 roflumilastparticles precipitated in a cream composition with both diethyleneglycol monoethyl ether (DEGEE) and hexylene glycol. The three largestroflumilast particles were measured (0.05 mm×0.03 mm; 0.05 mm×0.03 mmand 0.05 mm×0.03 mm) and found to have a mean surface area of 1,500square microns.

FIG. 12 is a line graph comparing the pharmacokinetic (PK) profile oftwo formulations of the invention, Formulation 3 and Formulation 4, anda PK profile of a formulation of the prior art, Formulation 5.

FIG. 13 is a graph comparing the slow rise to Cmax of Formulation 4(dicetyl phosphate/ceteth-10 phosphate) with the significantly greaterroflumilast Cmax peak values (compared to trough T=0 plasmaconcentrations) following dosing with comparative formulation 5(potassium cetyl phosphate) and comparative formulation 6 (CetostearylAlcohol and Glyceryl Stearate/PEG-100 Stearate).

FIG. 14 is a line graph showing Day 1 and Day 28 PK profiles after oncedaily dosing of 0.15% roflumilast topical cream.

FIG. 15 is a line graph showing Day 1 and Day 14 PK profiles after oncedaily dosing of 0.3% roflumilast topical cream.

FIG. 16 is a line graph showing Day 1 and Day 28 PK profiles after oncedaily dosing of 0.5% roflumilast topical cream.

FIG. 17 is a line graph showing Day 1 and Day 28 PK profiles after oncedaily dosing of 1.0% roflumilast topical cream.

FIGS. 18A, 18B and 18C show changes in baseline in Target PlaqueSeverity Score and/or Target Plaque Area for 0.15% roflumilast topicalcream and 0.5% roflumilast topical cream.

FIGS. 19A and 19B show roflumilast and roflumilast N-oxide plasmaconcentrations at day 1 and day 28 (pharmacokinetic population) for0.15% roflumilast topical cream and 0.5% roflumilast topical cream.

FIGS. 20A and 20B are line graphs showing day 1 and day 8 PK profilesafter once daily dosing of Crodafos-CES creams containing either 0.3%crisaborole or 0.3% roflumilast.

FIG. 21 is a line graph comparing roflumilast plasma concentration overtime after 500 mcg once daily oral roflumilast (closed circles) andtopical 0.5% ARQ-151 cream (closed squares) 0-24 hours on day 28 of oncea day dosing. The oral roflumilast data (closed circles) was extractedfrom a plot in the publication T. D Bethke and G. Lahu, 2011, Int J ofClin Pharm and Ther, 49(1):51-57. [n=20 subjects; Time=0 (day 28pre-dose blood draw) 1.33 ng/mL; Time=1.0 hour 1.34 ng/mL; Time=2.0 hour1.26 ng/mL; Time=4.0 hour 1.18 ng/mL; Time=6.0 hour 1.25 ng/mL;Time=24.0 hour 1.15 ng/mL].

DETAILED DESCRIPTION OF THE INVENTION

The term “roflumilast” as used in this application refers toroflumilast, its salts, the N-oxide of roflumilast, and its salts unlessspecified otherwise or unless it is clear in context that reference isto roflumilast itself. The terms “N-oxide of roflumilast” and “salts ofeither roflumilast or of the N-oxide of roflumilast” refer specificallyto the N-oxide or salts of either roflumilast or the N-oxide thereof.Roflumilast formulations can be prepared by methods known in the art(e.g. see the '298 patent and U.S. application Ser. No. 14/075,035).

Roflumilast is a compound of the formula (I)

-   -   wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3        is 3,5-dichloropyrid-4-yl.

This compound has the chemical nameN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamid-e(INN: roflumilast).

The term “salts”, when referring to roflumilast or the N-oxide ofroflumilast, means a salt as described in paragraphs and of U.S. PatentApplication Publication No. US 2006/0084684, the disclosure of which isincorporated herein by reference.

Hexylene glycol (PharmaGrade. USP/NF) is 2-methyl-2,4-pentanediol of theformula (II).

One aspect of present invention is directed to the addition of hexyleneglycol to a roflumilast-containing pharmaceutical composition thatcontains a pharmaceutically acceptable solvent, including water, toinhibit growth of roflumilast crystals in the composition. For topicalproducts designed to contain suspended roflumilast particles orcrystals, the addition of hexylene glycol to a composition containingroflumilast, will inhibit (i.e., prevent or substantially reduce incomparison to compositions that do not contain a hexylene glycol)changes in particle size distribution over the shelf life of the productand assure consistent bioavailability. For topical products designed tohave roflumilast completely dissolved, hexylene glycol inhibits thegrowth of precipitated roflumilast particles.

Drug products that have fully dissolved drug substance for the labeledstorage conditions over product shelf life will have the activeprecipitate if the product is formulated to maintain significantthermodynamic driving force. Typical storage conditions for a topicalpharmaceutical cream are: Store at room temperature: 60° F./15° C.-80°F./26° C. Do not freeze. It is understood by product developmentscientists and regulatory agency reviewers that a topical product willnot always be stored over this temperature range. Therefore, the FDArequires that all topical products undergo freeze-thaw cycling andtemperature excursion studies. The active is neither required norexpected to remain in solution when the product is exposed totemperatures of −20° C., dramatically below 15° C. (60° F.) of thelabeled storage condition. Since topical products containing completelydissolved drug are usually formulated near saturation, i.e. near maximumthermodynamic driving force, most topical products experienceprecipitation of the active ingredient during freeze-thaw cycling ortemperature excursion studies. The addition of hexylene glycol preventscrystal growth of roflumilast when precipitation occurs due totemperature excursions below the labeled storage conditions. Inhibitingcrystal growth assures that any precipitated active will quickly returnto being completely dissolved once the product is returned to controlledroom temperature. The prompt return of the precipitated roflumilast to afully dissolved state assures consistent, reproducible bioavailability,efficacy and safety of the topically applied product. Hexylene glycolcan be added between 0.1% and 20% on a weight/weight basis, preferablybetween 0.25% and 8% on a weight/weight basis and most preferablybetween 0.5% and 2% on a weight/weight basis.

The topical roflumilast product formulations that benefit from theaddition of hexylene glycol include but are not limited to aerosols,foams, sprays, emulsions (which can also be called creams, lotions, orointments), gels (two phase or single phase), liquids, ointments,pastes, shampoos, suspensions, and systems. These are the tier two termswithin compendia taxonomy for dosage forms containing pharmaceuticalactive ingredients (US Pharmacopeia <1151>).

In a second aspect of the present invention, it has been unexpectedlydiscovered that, in direct contrast to the dogma of the prior art, apharmaceutical formulation, such as a topically applied pharmaceuticalformulation containing roflumilast, provides an altered PK(pharmacokinetic) profile with a reduced Cmax or a reduced absorptionrate to reach Cmax when the formulations contain one or more phosphateester surfactants compared to pharmaceutical formulations containingroflumilast without a phosphate ester surfactant(s). In particular, ithas been unexpectedly discovered that a pharmaceutical formulationcontaining roflumilast and one or more phosphate ester surfactants, whentopically administered to an individual, provides a systemicallyeffective level of the PDE-4 inhibitor comparable to, or even greaterthan, that achieved with oral administration by slow absorption andwithout a Cmax spike of the PDE-4 inhibitor into the bloodstream.

In pharmacokinetic terms, a formulation containing roflumilast, and aphosphate ester surfactant, when administered to an individual, such asby applying topically to the skin of an individual, provides asufficiently high Area Under the Curve (AUC) to attain a systemicallyeffective level of roflumilast without rapidly producing a peak plasmaconcentration (Cmax) that is associated with gastrointestinal sideeffects. That is, the absorption rate of the drug to reach Cmax isdecreased when the formulation of the present application isadministered, compared with the administration of formulations of theprior art.

As used herein, the term “absorption rate to reach Cmax” means the slopeof the PK curve between the administration of a formulation containingdrug until Cmax, or the slope of the PK curve between a trough and theadjacent peak following serial multiple dose administrations of theformulation.

Thus, in contrast to the teachings of the prior art, the formulations ofthe present application unexpectedly have a markedly different PKprofile compared to prior art formulations containing roflumilast. Theformulations of the present application provide a sufficiently high AUCto attain a systemically effective level of roflumilast withoutproducing a spike in Cmax. The gradual ascent to Cmax obtained followingtopical application of the formulations of the present invention ismarkedly different from that of prior art formulations, but the AUC issimilar. Additionally, following multiple doses of the formulation, thePK profile lacks the initial Cmax spike and the peak to trough patternthat is obtained following multiple daily dosing with prior artformulations containing the drug.

This discovery provides several unexpected advantages. Primarily, itprovides a means for treatment of medical conditions that are responsiveto the administration of roflumilast, while minimizing the incidence ofundesirable side effects, especially GI side effects. This in turn leadsto greater patient compliance and reduced incidence of cessation oftreatment due to the development of such side effects.

Furthermore, because the ascent to Cmax is relatively slow, and a rapidCmax spike is avoided, the formulations of the present invention canresult in higher systemic exposure levels (AUC) than are possible withprior art formulations and without the side effects associated with aCmax spike, such as those of the G.I. system. Such previouslyunobtainable exposure levels will provide a greater efficacy in thetreatment of diseases.

Moreover, it has been unexpectedly discovered that, following theattainment of Cmax after administration, there is a very flat andprolonged plateau in blood levels of the drug. Additionally, the PKprofile obtained after multiple doses of the formulation of the presentapplication is extremely and unexpectedly flat and prolonged with anextremely small peak to trough fluctuation following administration for28 days. This flatness of the PK profile is especially pronounced whenthe formulation further contains diethylene glycol monoethyl ether.

Because the absorption of roflumilast from the formulation in an amountrequired to provide a therapeutic effect is not dependent on a spike inabsorption to provide a high Cmax and because the absorption ofroflumilast is stable and has a flat PK profile, an individual user of aformulation producing such a PK profile may miss one or more doses fromtime to time and still maintain efficacy of the treatment.

An important advantage of the present invention is that, a slow ascentto Cmax without a concomitant Cmax spike permit the obtaining of highersystemic exposure levels (AUC) than are possible with prior artformulations and without the side effects associated with Cmax spike,such as those of the G.I. system. Such previously unobtainable exposurelevels will provide a greater efficacy in the treatment of diseases.

A pharmaceutical formulation of the present invention containsroflumilast in a concentration which is sufficient to ameliorate amedical condition that is responsive to the administration of a PDE-4inhibitor drug, such as psoriatic arthritis, psoriasis, atopicdermatitis, asthma and COPD. The concentration of roflumilast, in theformulation is that which is sufficient to obtain a desired systemicpharmacologic effect when the formulation is applied to the skin of anindividual. This concentration will necessarily differ based on the typeof formulation and the disease or condition to be treated. Theconcentration of roflumilast within the formulation is typically in therange of 0.001 to 25% w/w, with a preferred range between 0.01 to 5%, amore preferred range between 0.05 and 1%, and a most preferred rangebetween 0.1 and 0.5%. In a particular preferred embodiment, theconcentration of roflumilast in the formulation is between 0.05 and0.5%, such as 0.05%, 0.15%, 0.3%, and 0.5% w/w.

The formulation may contain a means for inhibiting crystal growth andchanges in particle size dis0.tribution which can be hexylene glycol.The formulation may further contain a means for providing a sufficientlyhigh AUC to attain a systemically effective level of roflumilast withoutproducing a spike in Cmax, which can be one or more phosphate estersurfactants. Examples of phosphate ester surfactants that may beincluded in the formulations of this application include but are notlimited to potassium cetyl phosphate, potassium C9-15 alkyl phosphate,potassium C11-15 alkyl phosphate, potassium C12-13 alkyl phosphate,potassium C12-14 alkyl phosphate, potassium lauryl phosphate, C8-10alkyl ethyl phosphate, C9-15 alkyl phosphate, C20-22 alkyl phosphate,castor oil phosphate, ceteth-10 phosphate, cetheth-20 phosphate,ceteth-8 phosphate, cetearyl phosphate, cetyl phosphate, dimethiconePEG-7 phosphate, disodium lauryl phosphate, disodium oleyl phosphate,lauryl phosphate, myristyl phosphate, octyldecyl phosphate, oleth-10phosphate, oleth-5 phosphate, oleth-3 phosphate, oleyl ethyl phosphateoleyl phosphate, PEG-26-PPG-30 phosphate, PPG-5 ceteareth-10 phosphate,PPG-5 ceteth-10 phosphate, sodium lauryl phosphate, sodium laureth-4phosphate, steartyl phosphate, DEA-cetyl phosphate, DEA-oleth-10phosphate, DEA-oleth-3 phosphate, DEA-C8-C18 perfluoroalkylethylphosphate, dicetyl phosphate, dilaureth-10 phosphate, dimyristylphosphate, dioleyl phosphate, tricetyl phosphate, triceteareth-4phosphate, trilaureth-4 phosphate, trilauryl phosphate, triolyeylphosphate and tristearyl phosphate.

The concentration of the phosphate ester surfactant in the formulationis that which is sufficient to produce a stable emulsion having uniformglobule size. If desired, lower concentrations of the phosphate estersurfactant may be combined with other emulsifiers to produce a stableemulsion having uniform globule size. The phosphate ester surfactant mayalso increase the solubility of the roflumilast in the cream. Theconcentration of the phosphate ester surfactant generally may be anyconcentration between 1.0% to 25% w/w. The preferred concentration canbe different for different administration forms. In a preferredembodiment, when the formulation is a cream or ointment, theconcentration of the phosphate ester surfactant is between 2.5% and 20%,with a more preferred concentration range between 5% and 15%, and a mostpreferred concentration being about 10% w/w. When the formulation is inthe form of a foam, the concentration is preferably between 1.0%-10%,more preferably between 1.0%-10%, and most preferably 2%.

The formulation can optionally contain, a means for increasing thesolubility of roflumilast, which can be diethylene glycol monoethylether. Diethylene glycol monoethyl ether is also known as2-(2-ethoxyethoxy)ethanol, or as DEGEE, and is marketed under theseveral tradenames, including TRANSCUTOL® (Gattefosse Corporation,Paramus, NJ), CARBITOL™ (The Dow Chemical Company, Midland, MI),DIOXITOL® (Shell Oil Company, Houston, TX), and POLY-SOLV DM (MonumentChemical, Houston, TX).

DEGEE is often added to topical products as a co-solvent to increasesolubility of the drug in the formulation. Addition of DEGEE to atopical formulation has also been shown to enhance skin penetration,i.e. increase Cmax, of topically administered pharmaceutical actives.See D. W. Osborne and J. Musakhanian, “Skin Penetration and PermeationProperties of TRANSCUTOL®—Neat or Diluted Mixtures”, AAPS Pharm SciTech.19(8):3512-3533 (2018) DOI: 10.1208/s12249-018-1196-8; and Javadzadeh etal, Chapter 12 pages 195-205, in Percutaneous Penetration EnhancersChemical Methods in Penetration Enhancement: Modification of the StratumCorneum (N. Dragicevic, H. I. Maibach, eds) Springer-Verlag BerlinHeidelberg 2016.

The concentration of the diethylene glycol monoethyl ether, if present,in the formulation is that which is sufficient to dissolve the activepharmaceutical ingredient. Diethylene glycol monoethyl ether may alsoenhance the skin penetration of the roflumilast. Generally, theconcentration of the diethylene glycol monoethyl ether is between 5% and50% w/w, with a preferred range of concentrations between 10% and 40%w/w, a more preferred range between 15% and 30% w/w, and a particularpreferred concentration being about 15-25% w/w. Likewise, water isformulated as about 20-90% (w/w) in topical products. For blends ofDEGEE and water the ratio can range from 1:10 to 20:1. Preferably theDEGEE:water ratio is 1:4 to 9:1 in a formulation containing roflumilast.Generally, DEGEE-water blends can be used to dissolve up to 2.0%roflumilast (in the finished product) or preferably up to 0.5%roflumilast (in the finished product).

The formulation for topical application to the skin is preferably asemi-solid dosage form that is cosmetically acceptable for use on theskin and which is easily spreadable on the skin. Examples of suchsemi-solid dosage forms include emulsions, ointments, creams, gels, andpastes. The formulation may alternatively be in a form other than asemi-solid dosage form, such as a liquid, which may be administered as aspray, or a foam. Preferably, a formulation for topical administrationis in one of the following forms:

An oil-in-water emulsion: The product may be formulations in whichhexylene glycol is added to an emulsion comprising a discrete phase of ahydrophobic component and a continuous aqueous phase that includes waterand optionally one or more polar hydrophilic excipients as well assolvents, co-solvents, salts, surfactants, emulsifiers, and othercomponents. These emulsions may include water-soluble or water-swellablepolymers that help to stabilize the emulsion.

A water-in-oil emulsion: The compositions may be formulations in whichroflumilast is incorporated into an emulsion that includes a continuoushydrophobic phase and an aqueous phase that includes the DEGEE-waterblend and optionally one or more polar hydrophilic carrier(s) as well assalts or other components. These emulsions may include oil-soluble oroil-swellable polymers as well as one or more emulsifier(s) that help tostabilize the emulsion.

For both oil-in-water and water-in-oil emulsions, order of addition maybe important. Roflumilast can be added pre-dissolved in the continuousaqueous phase containing the DEGEE-water blend. Likewise, roflumilastcan be pre-dissolved in the hydrophobic discrete phase of the emulsionthat is then mixed with the DEGEE-water blend and optional hydrophilicexcipients that do not contain the active ingredient. Roflumilast can bepre-dissolved in both the oil phase and water phase of the emulsion oradded pre-dissolved in DEGEE or a DEGEE-water blend after the emulsionhas been formed. Some emulsions undergo phase inversion over a specifictemperature range during cooling of the emulsion. Thus, roflumilast maybe added to a water-in-oil emulsion above the phase inversiontemperature, with the final drug product being an oil-in-water emulsionat controlled room temperature, or vice versa.

Thickened Aqueous gels: These systems include the DEGEE-water blend withdissolved roflumilast and optionally one or more polar hydrophiliccarrier(s) such as hexylene glycol which has been thickened by suitablenatural, modified natural, or synthetic thickeners such as describedbelow. Alternatively, the thickened aqueous gels can be thickened usingsuitable polyethoxylate alky chain surfactants or other nonionic,cationic, or anionic systems.

Thickened Hydroalcoholic gels: These systems include a blend of waterand alcohol as the polar phase which has been thickened by suitablenatural, modified natural, or synthetic polymers such as describedbelow. Alternatively, the thickened hydroalcoholic gels can be thickenedusing suitable polyethoxylate alky chain surfactants or other nonionic,cationic, or anionic systems. The alcohol can be ethanol, isopropylalcohol or other pharmaceutically acceptable alcohol.

Hydrophilic gels: These are systems in which the continuous phaseincludes at least one water soluble or water dispersible hydrophiliccomponent other than water. The formulations may optionally also containwater up to 60% by weight. Higher levels may be suitable in somecompositions. Suitable hydrophilic components include one or moreglycols such as polyols such as glycerin, propylene glycol, butyleneglycols, polyethylene glycols (PEG), random or block copolymers ofethylene oxide, propylene oxide, and/or butylene oxide, polyalkoxylatedsurfactants having one or more hydrophobic moieties per molecule,silicone copolyols, blend of ceteareth-6 and stearyl alcohol as well ascombinations thereof, and the like.

A hydrophilic or hydrophobic ointment: The compositions are formulatedwith a hydrophobic base (e.g. petrolatum, thickened or gelled waterinsoluble oils, and the like) and optionally having a minor amount of awater soluble phase. Hydrophilic ointments generally contain one or moresurfactants or wetting agents

Solvents

Compositions according to the present invention may include a means forobtaining the desired level of active ingredient solubility in thetopical product which can be one or more solvents or co-solvents. Thesolvent may also modify skin permeation or the activity of otherexcipients contained in the formulation. Means for obtaining the desiredlevel of active ingredient solubility in the topical product include butare not limited to acetone, ethanol, benzyl alcohol, butyl alcohol,diethyl sebacate, diethylene glycol monoethyl ether, diisopropyladipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropylisostearate, isopropyl myristate, N-methyl pyrrolidinone, polyethyleneglycol, glycerol, propylene glycol and SD alcohol.

Moisturizers

Compositions according to the present invention may include amoisturizer to increase the level of hydration. For emulsions, themoisturizer is often a component of the discrete or continuoushydrophobic phase. The moisturizer can be a hydrophilic materialincluding humectants or it can be a hydrophobic material includingemollients. Suitable moisturizers include but are not limitedto:1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin,polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetylalcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil,cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate,fatty acids, glyceryl isostearate, glyceryl laurate, glycerylmonostearate, glyceryl oleate, glyceryl palmitate, glycol distearate,glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineraloil, light mineral oil, lanolin limonene, medium-chain triglycerides,menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol,oleyl oleate, olive oil, paraffin, peanut oil, petrolatum,Plastibase-50W, sorbitol, stearic acid, urea and stearyl alcohol.

Surfactants and Emulsifiers

Compositions according to the present invention optionally can includeone or more surfactants to emulsify the composition and to help wet thesurface of the actives or excipients. As used herein the term“surfactant” means an amphiphile (a molecule possessing both polar andnonpolar regions which are covalently bound) capable of reducing thesurface tension of water and/or the interfacial tension between waterand an immisicible liquid. Surfactants include but are not limited toalkyl aryl sodium sulfonate, Amerchol-CAB, ammonium lauryl sulfate,apricot kernel oil PEG-6 esters, Arlacel, benzalkonium chloride,Ceteareth-6, Ceteareth-12, Ceteareth-15, Ceteareth-30, cetearylalcohol/ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-10phosphate, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide ethersulfate, cocamine oxide, coco betaine, coco diethanolamide, cocomonoethanolamide, coco-caprylate/caprate, dicetyl phosphate, disodiumcocoamphodiacetate, disodium laureth sulfosuccinate, disodium laurylsulfoacetate, disodium lauryl sulfosuccinate, disodium oleamidomonoethanolamine sulfosuccinate, docusate sodium, laureth-2, laureth-23,laureth-4, lauric diethanolamide, lecithin, mehoxy PEG-16, methylgluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2,oleth-20, PEG 6-32 stearate, PEG-100 stearate, PEG-12 glyceryl laurate,PEG-120 methyl glucose dioleate, PEG-15 cocamine, PEG-150 distearate,PEG-2 stearate, PEG-20 methyl glucose sesqustearate, PEG-22 methylether, PEG-25 propylene glycol stearate, PEG-4 dilaurate, PEG-4 laurate,PEG-45/dodecyl glycol copolymer, PEG-5 oleate, PEG-50 Stearate, PEG-54hydrogenated castor oil, PEG-6 isostearate, PEG-60 hydrogenated castoroil, PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate,Pegoxol 7 stearate, pentaerythritol cocoate, poloxamer 124, poloxamer181, poloxamer 182, poloxamer 188, poloxamer 237 poloxamer 407,polyglyceryl-3 oleate, polyoxyethylene alcohols, polyoxyethylene fattyacid esters, polyoxyl 20 cetostearyl ether, polyoxyl 40 hydrogenatedcastor oil, polyoxyl 40 stearate, polyoxyl 6 and polyoxyl 32, polyoxylglyceryl stearate, polyoxyl stearate, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 65, polysorbate 80, PPG-26 oleate,PROMULGEN™ 12, propylene glycol diacetate, propylene glycol dicaprylate,propylene glycol monostearate, sodium xylene sulfonate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2,steareth-20, steareth-21, steareth-40, tallow glycerides, andemulsifying wax.

Phosphate ester surfactants can also act as a means for reducing a spikein Cmax while producing an AUC sufficient to attain a systemicallyeffective level of roflumilast. Suitable phosphate ester surfactantsinclude but are not limited to potassium cetyl phosphate, potassiumC9-15 alkyl phosphate, potassium C11-15 alkyl phosphate, potassiumC12-13 alkyl phosphate, potassium C12-14 alkyl phosphate, potassiumlauryl phosphate, C8-10 alkyl ethyl phosphate, C9-15 alkyl phosphate,C20-22 alkyl phosphate, castor oil phosphate, ceteth-10 phosphate,cetheth-20 phosphate, ceteth-8 phosphate, cetearyl phosphate, cetylphosphate, dimethicone PEG-7 phosphate, disodium lauryl phosphate,disodium oleyl phosphate, lauryl phosphate, myristyl phosphate,octyldecyl phosphate, oleth-10 phosphate, oleth-5 phosphate, oleth-3phosphate, oleyl ethyl phosphate oleyl phosphate, PEG-26-PPG-30phosphate, PPG-5 ceteareth-10 phosphate, PPG-5 ceteth-10 phosphate,sodium lauryl phosphate, sodium laureth-4 phosphate, steartyl phosphate,DEA-cetyl phosphate, DEA-oleth-10 phosphate, DEA-oleth-3 phosphate,DEA-C8-C18 perfluoroalkylethyl phosphate, dicetyl phosphate,dilaureth-10 phosphate, dimyristyl phosphate, dioleyl phosphate,tricetyl phosphate, triceteareth-4 phosphate, trilaureth-4 phosphate,trilauryl phosphate, triolyeyl phosphate and tristearyl phosphate.

Polymers and Thickeners

For certain applications, it may be desirable to formulate a productthat is thickened with soluble, swellable, or insoluble organicpolymeric thickeners such as natural and synthetic polymers or inorganicthickeners such as acrylates copolymer, carbomer 1382, carbomercopolymer type B, carbomer homopolymer type A, carbomer homopolymer typeB, carbomer homopolymer type C, carboxy vinyl copolymer,carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum,hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax,and methylcellulose.

The formulation may contain one or more thickening agent to provideviscosity so that the formulation may be provided in the form of asemisolid, such as a lotion, gel, cream, or ointment. Examples ofsuitable thickening agents include but are not limited to soluble,swellable, or insoluble organic polymeric thickeners such as natural andsynthetic polymers or inorganic thickeners including but not limited toacrylates copolymer, carbomer 1382, copolymer type B, carbomerhomopolymer type A, homopolymer type B, carbomer homopolymer type C,carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, microcrystalline wax, acacia, alginic acid,bentonite, carbomers, also known as carboxy vinyl polymers, such as soldunder the tradename Carbopol® (Lubrizol, Wickliffe, Ohio),carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose,hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose,poloxamers, polyvinyl alcohol, sodium alginate, tragacanth, and xanthangum. The thickening agent may reside in the oil or lipophilic portion ofthe formulation. Examples of suitable lipophilic thickening agentsinclude cetyl alcohol, stearyl alcohol, glyceryl stearate, whitebeeswax, microcrystalline wax, hydrogenated polyisobutane polymers, andemulsifying wax.

Additional Components

Compositions according to the present invention may be formulated withadditional components such as fillers, carriers and excipientsconventionally found in cosmetic and pharmaceutical topical products.Additional components including but not limited to foaming agents,propellants preservatives (e.g. p-hydroxybenzoic esters, benzyl alcohol,phenylmercury salts, chlorocresol), antioxidants, sequestering agents,stabilizers, buffers, pH adjusting solutions, skin penetrationenhancers, film formers, dyes, pigments, diluents, bulking agents,fragrances and other excipients to improve the stability or aestheticsof the product, may be added to the composition.

The formulation may contain other pharmaceutically acceptable excipientsif desired. For example, the formulation may contain a humectant such asglycerin, sorbitol, hexylene glycol, urea, or propylene glycol. Theformulation may contain an emollient such as petrolatum, lanolin,mineral oil, light mineral oil, stearic acid, cyclomethicone, ordimethicone. Additional optional excipients include stabilizers, foamingagents, preservatives such as methylparaben, pH adjusting agents such assodium hydroxide, chelating agents such as EDTA and its salts, andbuffers.

In one preferred embodiment, the roflumilast is in the form of anaerosolized foam which is particularly suitable for application to thescalp. Any suitable propellant can be used to prepare the aerosolizedfoam. Particularly preferred propellants are Isobutane A-31, Aeropin 35,Butane 48, Dimethyl Ether/N-Butane-(53/47), Propane/Iso-Butane/N-Butane,Propane/lsobutane-A70, and Propane/Isobutane A-46, N-Butane A-17.

Additional Active Agents

Compositions according to the present invention may be formulated withadditional active agents depending on the condition being treated. Theadditional active agents include but are not limited to NSAIDs (e.g.Aspirin, Ibuprofen, Ketoprofen, Naproxen), Apremilast and other PDE4inhibitors, JAK inhibitors (e.g. Tofacitinib, Ruxolitinib, Oclacit),leukotriene inhibitors (e.g. Zileuton, Zafirlukast, Montelukast), mastcell stabilizers (e.g. Nedocromil, Cromolyn sodium, Ketotifen,Pemirolast), Anthralin (dithranol), purine synthesis inhibitors (e.g.Azathioprine), Coal tar, Methotrexate, Methoxsalen, Salicylic acid,Ammonium lactate, Urea, Hydroxyurea, 5-fluorouracil, Propylthouracil,6-thioguanine, Sulfasalazine, Mycophenolate mofetil, Fumaric acidesters, Corticosteroids (e.g. Aclometasone, Amcinonide, Betamethasone,Clobetasol, Clocotolone, Mometasone, Triamcinolone, Fluocinolone,Fluocinonide, Flurandrenolide, Diflorasone, Desonide, Desoximetasone,Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone,Methylprednisolone, Prednicarbate, Prednisone), Corticotropin, Vitamin Danalogues (e.g. calcipotriene, calcitriol), retinoids (e.g., Acitretin,Tazarotene), calcineurin inhibitors (eg, cyclosporine, tacrolimus,pimecrolimus), Resorcinol, Colchicine, bronchodilators (e.g.beta-agonists, anticholinergics, theophylline), and antibiotics andother anti-infectives (e.g. erythromycin, ciprofloxacin, metronidazole,and anti-fungals such as miconazole and terbinafine).

Administration and Dosage

Suitable pharmaceutical dosage forms include but are not limited toemulsions, suspensions, sprays, oils, ointments, fatty ointments,creams, pastes, gels, foams transdermal patches and solutions (e.g.injectable, oral).

The composition preferably contains roflumilast, salts of roflumilast,the N-oxide of roflumilast or salts thereof in an amount of 0.005-2%w/w, more preferably 0.05-1% w/w, and most preferably 0.1-0.5% w/w perdosage unit.

The composition preferably contains a means for inhibiting crystalgrowth and changes in particle size which is preferably hexylene glycolin an amount of between 0.1% and 20% w/w, more preferably between 0.25%and 8% w/w and most preferably between 0.5% and 2% w/w.

The composition preferably contains one or more phosphate estersurfactants. The concentration of the phosphate ester surfactantgenerally may be any concentration between 1.0% to 25% w/w.

The composition preferably contains a component for increasing thesolubility of roflumilast, which is preferably diethylene glycolmonoethyl ether. The concentration of the diethylene glycol monoethylether may be any concentration between 5% and 50% w/w.

The topical formulation containing roflumilast, is applied to the skinin an amount that is sufficient to obtain the desired pharmacologiceffect, which typically is to ameliorate the signs and/or symptoms of amedical disorder. The amount of the formulation that is applied may varydepending on the concentration of roflumilast within the formulation,and the frequency with which the formulation is applied. Generally, theformulation is applied with a frequency between weekly to several timesdaily, preferably between every other day to three times daily, and mostpreferably one or two times daily.

The formulation containing roflumilast may be used in veterinary and inhuman medicine to treat a systemic medical condition that is amelioratedby or responsive to systemic administration of roflumilast. Non-limitingexamples of such medical conditions include but are not limited to acuteand chronic airway disorders such as bronchitis, allergic bronchitis,asthma, and COPD; proliferative, inflammatory and allergic dermatosessuch as psoriasis, scalp psoriasis, or inverse psoriasis, irritant andallergic contact eczema and other varieties of eczema, hand eczema,atopic dermatitis, seborrheic dermatitis, lichen simplex chronicus,sunburn, aphthous ulcers, lichen planus, vitiligo, pruritus in thegenital, anal or other body regions, alopecia areata, hypertrophicscars, discoid lupus erythematosus, follicular and extensive pyodermas,endogenous and exogenous acne, acne rosacea, disorders which are basedon an excessive release of TNF and leukotrienes, disorders of the heartwhich can be treated by PDE inhibitors, inflammations in thegastrointestinal system (including the liver) or central nervous system,disorders of the eye, disorders which can be treated by thetissue-relaxant action of roflumilast and other proliferative,inflammatory and allergic skin disorders; and immune mediated diseasessuch as arthritis including rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis, and psoriatic arthritis.

The systemic dose of a drug administered topically depends on theconcentration in the formulation, on the surface area to which the drugis applied and on the disease/anatomical site being treated. Forexample, the thick plaques of psoriasis decrease the systemic dose, butcracks and fissures in and around the plaques provide a shunt pathway toincrease the systemic dose. These effects tend to cancel each other outso that the systemic dose found after topically treating psoriasispatients over similar Body Surface Areas (% BSA) is similar to thesystemic dose obtained in treating normal volunteers. This also resultsin psoriatic patients tending to have the same systemic dose throughouttreatment duration even though their disease is steadily resolving tobecome clear or nearly clear. When skin afflicted with atopic dermatitis(AD) is treated, there is a much higher systemic dosing for threereasons: (1) AD skin has an inherent skin barrier defect that alwaysresults in a higher systemic dose after topical treatment, (2) higher %BSA areas require treatment in AD (>20% BSA) compared to psoriasis (onaverage 7% BSA) because AD covers more of the body's skin surface areathan psoriasis, and 3) psoriasis is primarily a disease of adults whileAD is a disease in children. The ratio of skin surface area to bodyweight is higher in a child compared to an adult.

Pediatric dosing of topical products such as roflumilast cream is muchsimpler than oral tablets because topical creams do not have rigid doseunits, and for children too young to self-administer product, theproduct does not need to be reformulated for a caregiver to administerthe product. The challenge in topically dosing children is that theratio of skin surface area to body weight changes dramatically frombirth to adulthood. This is a major concern when dosing neonates withtopical products, but of less concern when dosing children who are atleast 3-months old and proportionately less concern when dosingpediatric patients 2 years or older. The ratio of surface area to bodyweight for pediatric patients compared to an adult is shown below. Thegreater ratio of skin surface area to body weight corresponds to a lowervolume of distribution within the pediatric population after topicaladministration of the drug product. While the stratum corneum is intactshortly after birth (<1 month), the way human skin stores, andtransports water becomes adult-like only after the first year of life(Batchelor, et al., Formulations for children: problems and solutions,British Journal of Clinical Pharmacology, 79:3, pp. 405-418 2013. At twoyears of age, the stratum corneum is still thinner compared to an adult(10 μm compared to 12 μm) and thus barrier function is slightlydiminished (Walters, et al., Developmental Changes in Skin Barrier andStructure during the First 5 years of Life, Skin Pharmacol Physiol,29:111-118, 2016). By the time a child reaches 3-5 years of age the skinbarrier is similar to that of an adult.

Average (50 percentile) BSA and Body Weights in young children PatientAge Skin Surface Area Body Weight Ratio Child to Adult{circumflex over( )} Neonate 2,100 cm²   3.4 kg 2.4 3-months 3,400 cm²   6 kg 2.22-years 5,000 cm² 12.4 kg 1.6 of 66 kg and BSA of 17,000 cm²

The lower volume of distribution in the very young pediatric populationcompared to an adult results in children experiencing a higher systemicdose compared to an adult administered the exact same drug concentrationapplied over the same body surface area afflicted with the same severityof skin disease. A higher systemic dose in children can lead to anincrease in adverse events such as psychiatric, weight loss andgastrointestinal side effects. The present formulations for topicalapplication are suitable for administration to atopic dermatitispatients as young as 3 months and psoriasis patients as young as 2 yearsof age due to a roflumilast release profile that produces a flattenedplasma concentration time curve and a reduced Cmax thereby decreasingadverse events in pediatric populations.

The formulation for topical application containing roflumilast, may beprepared by processes typically used in the field of manufacture ofpharmaceutical formulations for topical application. In order to make asingle-phase formulation, such as a liquid, the constituents of theformulation may be combined and mixed until a homogenous solution orsuspension of the active ingredient is obtained. In order to make amultiphase formulation such as an emulsion, for example, the componentsof the aqueous phase and of the oil phase may be separately combined andmixed until homogenous solutions are obtained and then the aqueoussolution and the oil solution may be combined and mixed, such as byshear mixing, to form the formulation. The one or more drug actives maybe dissolved (molecularly dispersed), complexed, or associated with anexcipient or other active, or may be particulate (amorphous orcrystalline). The oil phase may be added to the water phase, or thewater phase may be added to the oil phase. The phases may be combinedand mixed, such as at elevated temperatures of 50-90° C. or at roomtemperature, that is between 20-30° C., or at a temperature between roomtemperature and the elevated temperatures.

The following examples are provided to enable those of ordinary skill inthe art to make and use the methods and compositions of the invention.These examples are not intended to limit the scope of what the inventorregards as the invention. Additional advantages and modifications willbe readily apparent to those skilled in the art.

In the following examples, Crodafos™ CES (Croda Inc., Edison, NJ),containing the phosphate ester surfactants dicetyl phosphate andceteth-10 phosphate, is utilized as a representative example ofphosphate ester surfactants.

EXAMPLE 1

A few mg of roflumilast API (Batch A14367P from Interquim S.A.) drypowder was tapped onto a microscope slide, a coverslip was moved intoplace and crystal habit and particle size of the API were examined usingpolarized light microscopy using a 10× objective (FIG. 1 , microscopesample 19-2).

0.0092 grams of roflumilast (Batch A14367P from Interquim S.A.) wasweighed into a liquid scintillation vial. An equimolar blend of hexyleneglycol (lot 1AC0818, Spectrum) and distilled water was added dropwisewith mixing to the vial containing roflumilast to produce a suspensionof roflumilast in excess of the solubility limit. An equimolar blend is86.7% hexylene glycol and 13.3% water on a weight/weight percent basis.After mixing each addition of hexylene glycol:water blend, the tightlycapped vial was returned to a water bath set at 25° C. It required0.7962 grams of equimolar Hexylene Glycol:Water blend to completelydissolve the 0.0092 grams of roflumilast and give a 1.14% roflumilast inequimolar Hexylene Glycol:Water (wt/wt %) solution. 0.0064 grams ofroflumilast was added to this sample (labeled 12-3) to form a finelydispersed suspension at 25° C. and the vial was then stored undisturbedat about 15-18° C., protected from the light for six weeks. A sample ofthe roflumilast crystals was removed from the vial, placed on amicroscope slide (with coverslip) and then examined using polarizedlight microscopy using a 10× objective (FIG. 2 , microscope sample20-3).

0.0111 grams of roflumilast (Batch A14367P from Interquim S.A.) wasweighed into a liquid scintillation vial. An equimolar blend ofdiethylene glycol (DEGEE) (Transcutol P, lot 146063, Gattefosse) anddistilled water was added dropwise with mixing to the vial containingroflumilast to produce a suspension of roflumilast in excess of thesolubility limit. An equimolar blend is 88.3% DEGEE and 11.7% water on aweight/weight percent basis. After mixing each addition of DEGEE:waterblend, the tightly capped vial was returned to a water bath set at 25°C. It required 0.2477 grams of equimolar DEGEE:Water blend to completelydissolve the 0.0111 grams of roflumilast and give a 4.29% roflumilast inequimolar DEGEE:Water (wt/wt %) solution. This sample (labeled 13-1) wasa solution of roflumilast at 25° C. and the vial was then storedundisturbed at about 15-18° C., protected from the light for six weeks.Roflumilast crystals precipitated due to the cooler storage temperature.A sample of the roflumilast crystals was removed from the vial, placedon a microscope slide (with coverslip) and then examined using polarizedlight microscopy using a 10× objective (FIG. 3 , microscope sample20-2).

EXAMPLE 2

0.0092 grams of roflumilast (Batch A14367P from Interquim S.A.) wasweighed into a liquid scintillation vial. An equimolar blend of hexyleneglycol (lot 1AC0818, Spectrum) and distilled water was added dropwisewith mixing to the vial containing roflumilast to produce a suspensionof roflumilast in excess of the solubility limit. An equimolar blend is86.7% hexylene glycol and 13.3% water on a weight/weight percent basis.After mixing each addition of hexylene glycol:water blend, the tightlycapped vial was returned to a water bath set at 25° C. It required0.7962 grams of equimolar Hexylene Glycol:Water blend to completelydissolve the 0.0092 grams of roflumilast and give a 1.14% roflumilast inequimolar Hexylene Glycol:Water (wt/wt %) solution. 0.0064 grams ofroflumilast was added to this sample (labeled 12-3) to form a finelydispersed suspension at 25° C. and the vial was then stored undisturbedat about 15-18° C., protected from the light for six weeks. A sample ofthe roflumilast crystals was removed from the vial, placed on amicroscope slide (with coverslip) and then examined using polarizedlight microscopy using a 4× objective (FIG. 4 , microscope sample 20-3).

0.0260 grams of roflumilast (Batch A14367P from Interquim S.A.) wasweighed into a liquid scintillation vial. 1.0705 grams of anethanol:water blend (Everclear which is 74.98% ethanol and 25.02% wateron a weight/weight percent basis or 95% alcohol by volume) was added toproduce a dispersion of roflumilast in an ethanol:water blend in excessof the solubility limit. This sample (labeled as “Alc” page 2) was thenstored undisturbed at about 15-18° C., protected from the light for sixweeks. A sample of the roflumilast crystals was removed from the vial,placed on a microscope slide (with coverslip) and then examined usingpolarized light microscopy using a 4× objective (FIG. 5 , microscopesample 20-3).

0.0180 grams of roflumilast (Batch A14367P from Interquim S.A.) wasweighed into a liquid scintillation vial. Polyethylene glycol 400 (lot1DE0880, Spectrum) was added dropwise with mixing to the vial containingroflumilast to produce a suspension of roflumilast in excess of thesolubility limit. After mixing each addition of polyethylene glycol 400,the tightly capped vial was returned to a water bath set at 25° C. Itrequired 0.5486 grams of propylene glycol 400 to completely dissolve the0.0180 grams of roflumilast and give a 3.18% roflumilast in polyethyleneglycol 400 solution. This sample (labeled as “PEG 400” page 1) was asolution at 25° C. and was then stored undisturbed at about 15-18° C.,protected from the light for six weeks. Roflumilast crystalsprecipitated due to the cooler storage temperature. A sample of theroflumilast crystals was removed from the vial, placed on a microscopeslide (with coverslip) and then examined using polarized lightmicroscopy using a 4× objective (FIG. 6 , microscope sample 21-3).

0.0103 grams of roflumilast (Batch A14367P from Interquim S.A.) wasweighed into a liquid scintillation vial and mixed with 0.2501 grams ofdimethyl sulfoxide (lot US150, Gaylord Chemical) to give a 28.5%solution of roflumilast at 25° C. This sample (labeled as “DMSO” page 2)was then stored undisturbed at about 15-18° C., protected from the lightfor six weeks. A sample of precipitated roflumilast crystals was removedfrom the vial, placed on a microscope slide (with coverslip) and thenexamined using polarized light microscopy using a 4× objective (FIG. 7 ,microscope sample 21-4).

0.0061 grams of roflumilast (Batch A14367P from Interquim S.A.), 1.9332grams of propylene glycol (lot 1EC0004, Spectrum) and 0.2335 gramsdistilled water was mixed to initially form a clear solution at 25° C.The composition of the sample was roflumilast, 88.97% propylene glycoland 10.75% water on a weight/weight basis. After 105 minutes of storageat 25° C. a “dusting” of fine roflumilast crystals were observed on thebottom of the vial. Six days later additional crystals had settled tothe bottom of the vial. This sample (labeled 7-2) was then storedundisturbed at about 15-18° C., protected from the light for six weeks.A sample of precipitated roflumilast crystals was removed from the vial,placed on a microscope slide (with coverslip) and then examined usingpolarized light microscopy using a 4× objective (FIG. 8 , microscopesample 21-5).

EXAMPLE 3

Dramatically greater roflumilast crystalline growth was observed in anequimolar N-methyl pyrrolidone:water solution containing roflumilast inexcess of drug saturation compared to a 12:4:3 (wt/wt/wt) blend ofhexylene glycol:N-methyl pyrrolidone:water (1.2 mole fraction of water)solution having roflumilast added in excess of the solubility limit.

0.0202 grams of roflumilast (Batch A14367P from Interquim S.A.) wasmixed with 0.0682 grams of equimolar N-Methyl-2-pyrrolidone:water blendin a liquid scintillation vial. An equimolar blend is 84.5%N-Methyl-2-pyrrolidone (lot SYYN-HJ, TCI) and water on a weight/weightpercent basis. The 22.85% roflumilast in equimolar N-Methyl-2pyrrolidone:water was completely dissolved at 25° C. This sample(labeled 13-2) was then stored undisturbed at about 15-18° C., protectedfrom the light for six weeks. Roflumilast crystals precipitated due tothe cooler storage temperature. A sample of the roflumilast crystals wasremoved from the vial, placed on a microscope slide (with coverslip) andthen examined using polarized light microscopy using a 4× objective(FIG. 10 , microscope sample 20-1).

A 0.8152 gram sample of 3.6% roflumilast (Batch A14367P from InterquimS.A.), 60.8% hexylene glycol (lot 1AC0818, Spectrum), 20.0%N-Methyl-2-pyrrolidone (lot SYYN-HJ, TCI) and 15.6% distilled water wasmixed on a weight/weight percent basis. This sample (labeled 13-4) was afinely dispersed suspension of roflumilast at 25° C. The sample was thenstored undisturbed at about 15-18° C., protected from the light for sixweeks. A sample of the roflumilast crystals was removed from the vial,placed on a microscope slide (with coverslip) and then examined usingpolarized light microscopy using a 4× objective (FIG. 11 , microscopesample 21-1).

EXAMPLE 4

Roflumilast creams were prepared according to the followingformulations.

Formulation 1 (comparative) Roflumilast  0.5% w/w White Petrolatum 10.0%w/w Isopropyl Palmitate  5.0% w/w Crodafos CES 10.0% w/w Diethyleneglycol monoethyl ether   25% w/w (Transcutol P) Methylparaben  0.2% w/wPropylparaben 0.05% w/w Purified Water q.s. ad 100 (49.25%)

Formulation 2 Roflumilast  0.5% w/w White Petrolatum 10.0% w/w IsopropylPalmitate  5.0% w/w Crodafos CES 10.0% w/w Hexylene glycol  2.0% w/wDiethylene glycol monoethyl ether 25.0% w/w (Transcutol P) Methylparaben 0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (47.25%)

After preparation, 0.4222 grams of formulation 1 was sealed in a 1.0 mLCryoTube™ vial and labeled as 36-1. Likewise, 0.3961 grams offormulation 2 was sealed in a 1.0 mL CryoTube™ vial and labeled as 36-2.The two CryoTube™ vials were secured in an envelope end-to-end andplaced in the freezer for 17.5 hours. Quickly upon removal from thefreezer, a microscopic slide was prepared of each sample and after“thawing” the sample to room temperature (18° C.) a photomicrographimage was captured to characterize differences in precipitatedroflumilast crystal growth. See FIGS. 11A and 11B.

EXAMPLE 5 Formulations According to the Invention and of the Prior Art

A formulation of the invention, hereafter referred to as Formulation 3,was made by combining roflumilast with a phosphate ester surfactant andwater. The formulation was buffered with NaOH to obtain a pH of 6.5.

A formulation of the invention, hereafter referred to as Formulation 4,was made by combining the above constituents and adding diethyleneglycol monoethyl ether. This formulation was buffered with NaOH toobtain a pH of 6.5.

A formulation that is not of the invention, hereafter referred to asComparative Formulation 5, was made by combining roflumilast withdiethylene glycol monoethyl ether. This formulation was gelled withhydroxylpropyl cellulose so that it would have a similar viscosity andspread on the skin like the two phosphate ester surfactant emulsionFormulations 3, and 4. This semisolid formulation was likewise bufferedwith NaOH to obtain a pH of 6.5.

The compositions of these formulations are shown below in Table 1.

TABLE 1 Comparative Formulation 3 Formulation 4 Formulation 5Roflumilast 0.15% w/w 0.15% w/w 0.15% w/w Crodafos CES 10.0% w/w 10.0%w/w cetostearyl alcohol dicetyl phosphate ceteth-10 phosphate DiethyleneGlycol 25.0% w/w 25.0% w/w Monoethyl Ether, NF Hydroxypropyl  0.5% w/wCellulose 1N NaOH, NF q.s. ad pH 6.5 q.s. ad pH 6.5 q.s. ad pH 6.5Purified Water, USP q.s. ad 100% q.s. ad 100% q.s. ad 100%

EXAMPLE 6—SINGLE DOSE TESTING OF FORMULATIONS OF EXAMPLE 5

Male and female swine (Gottingen Minipig® breed) (Marshall BioResources,North Rose, NY) were ordered to weigh 8 to 12 kg at arrival. On the dayprior to administration of one of the topical cream semisolidformulations of Example 5 containing 0.15% roflumilast, the hair wasclipped from the back of each animal. The pigs were sedated for theshaving procedure. Care was taken to avoid abrading the skin.

Two (2) grams of one of the cream formulations of Example 5 for each kgof pig weight was distributed over the clipped skin area by gentleinunction with a glass stirring rod or stainless-steel spatula. Thecream formulation was applied evenly with a thin, uniform film beginningat the scapular region and moving caudally over the test site. The widthof the test site area was bilaterally divided by the spine. Six pigs (3males and 3 females) were administered a single dose of the Formulation4. Blood was sampled from the anterior vena cava through the thoracicinlet or other suitable vein pre-dose (time=0) and at 1, 2, 4, 8 and 24hours post dose administration. A one-week wash out (no product dosed)was sufficient to reduce plasma levels of roflumilast to zero asverified by the pre-dose (time=0) sample. After the washout period, asingle dose of formulation 3 was applied. After a second one-weekwashout period, a single dose of Formulation 5 was applied. Bloodsamplings were the same for all three groups. The results are showngraphically in FIG. 12 .

As shown in FIG. 12 , pigs dosed with Comparative Formulation 5 of theprior art showed a rapid spike to Cmax within 3 hours of dosing. Incontrast, pigs dosed with Formulation 3 of the invention containing thephosphate ester surfactant Crodafos CES showed little or no spike toCmax. Pigs dosed with Formulation 4 of the invention containing both aphosphate ester surfactant and diethylene glycol monoethyl ether, likethose dosed with Formulation 3, showed a reduced spike to Cmax ascompared to Formulation 5. However, the higher Cmax obtained withFormulation 4 was higher than that for Formulation 3.

The PK data results in the graph of FIG. 12 show that the single dose PKprofile data for the formulation containing phosphate ester surfactantslacks a significant spike to Cmax and has a low Cmax of 0.36 ng/mL,while maintaining a mean plasma concentration of 0.34 ng/ml through the4 hour sample point. This is in contrast to PK data for the DEGEEformulation that rapidly raises to a Cmax of 0.85 ng/ml at 2 hours andthen just as quickly drops to 0.57 ng/mL at 4 hours. When the phosphateester surfactant is added to DEGEE the formulation of the invention, itlacks a significant spike to Cmax and has a low Cmax, while maintainingAUC, in contrast to PK data for the DEGEE formulation which does notcontain phosphate ester surfactants. This PK data is especiallysurprising in view of the fact that the prior art (Bolle) teaches thatCmax and AUC are similar for topical preparations containingroflumilast, irrespective of the composition of the topical formulation.In contrast to what one would expect based on the teachings of the priorart, Formulation 3, containing phosphate ester surfactant, lacks asignificant spike to Cmax. Moreover, the mean plasma concentration of0.34 ng/ml was maintained throughout the 4 hour sample point. Incontrast, Formulation 5 containing diethylene glycol monoethyl ether butlacking a phosphate ester surfactant, showed a rapid spike rise to Cmaxof 0.85 ng/ml at two hours. When a phosphate ester surfactant wasutilized in combination with diethylene glycol monoethyl ether,Formulation 4 administration produced no significant spike to Cmax andhad a Cmax between those obtained with Formulations 3 and 5, whilemaintaining AUC.

EXAMPLE 7—FORMULATION OF THE INVENTION AND A FORMULATION OF THE CLOSESTPRIOR ART

A third embodiment of the invention, hereafter referred to asFormulation 6, was made by combining roflumilast at a concentration of0.3% w/w with a phosphate ester surfactant and water. The formulationwas buffered with NaOH to obtain a pH of 5.5. This formulation issimilar to Formulation 3 except that the concentration of roflumilast is0.3% rather than 0.15% and the emulsion is buffered to a pH value of 5.5rather than a pH value of 6.5.

A formulation that is not of the invention, hereafter referred to asComparative Formulation 7, was made by combining roflumilast at aconcentration of 0.3% containing a phosphate ester surfactant, apolyoxyl stearyl ether surfactant and diethylene glycol monoethyl ether,as well as other excipients. This formulation is a cream formulationcontaining a frequently used phosphate ester surfactant that is notCrodafos CES.

A formulation that is not of the invention, hereafter referred to asComparative Formulation 8, was made by combining roflumilast at aconcentration of 0.2%. This formulation is that of the closest prior artknown to the inventors and is disclosed in Example 3 of Bolle et al,U.S. Patent Application No. US 2006/0084684.

The compositions of these formulations are shown below in Table 2.

TABLE 2 Comparative Comparative Formulation 6 Formulation 7 Formulation8 Roflumilast  0.3% w/w  0.3% w/w  0.2% w/w Petrolatum, USP —  10.0% w/w— Isopropyl Palmitate, —  5.0% w/w — NF Medium-Chain — — 25.0% w/wTriglycerides Crodafos CES 10.0% w/w — — cetostearyl alcohol (6-8% w/w)dicetyl phosphate (1-2.5% w/w) ceteth-10 phosphate (1-2.5% w/w)Potassium Cetyl  2.0% w/w Phosphate Cetostearyl Alcohol  6.0% w/w  5.0%w/w Polyoxyl Stearyl Ether  2.0% w/w Glyceryl Stearate/ —  5.0% w/wPEG-100 Stearate Diethylene Glycol —  25.0% w/w — Monoethyl Ether, NFHexylene Glycol, NF —  2.0% w/w — Methylparaben, NF —  0.20% w/w —Propylparaben, NF — 0.050% w/w — 1N NaOH, NF q.s. ad pH 5.5 q.s. ad pH5.5 — Purified Water, USP q.s. ad 100% q.s. ad 100% q.s. ad 100% *Theexact ratio of cetostearyl alcohol to dicetyl phosphate to cetheth-10phosphate in Crodafos CES is consistent between batches of product butis not publicly disclosed by the manufacturer (Croda). The safety datasheet for Crodafos CES states that this emulsifier is composed of 60-80%cetostearyl alcohol, 10-20% dicetyl phosphate and 10-20% cetheth-10phosphate. To emphasize the similarity in composition betweenFormulation 4 (phosphate-ester surfactant blend) and ComparativeFormulation 5 (phosphate ester and nonionic surfactant blend) andComparative Formulation 6 (nonionic surfactant blend), the cetostearylalcohol portion of Crodafos CES is listed separately from the surfactantportion of Crodafos CES in Table 2.

Glyceryl Stearate/PEG-100 Stearate is the nomenclature used by the USFood and Drug Administration to describe the nonionic emulsifier blendsold using the tradename Arlacel® 165 and Tego Care® 150.

Medium-Chain Triglycerides is the nomenclature used by the US Food andDrug Administration to describe the cosmetic ingredient Capryli/CapricTriglyceride which is sold using tradenames including Miglyol® 812 andCrodamole GTCC.

EXAMPLE 8—14-DAY DOSE TESTING OF FORMULATIONS OF EXAMPLE 7

Male and female swine (Gottingen Minipig® breed) are ordered to weigh 8to 12 kg at arrival. On the day prior to administration of one of thetopical cream semisolid formulations of Example 7, the hair is clippedfrom the back of each animal. The pigs are sedated for the shavingprocedure. Care is taken to avoid abrading the skin.

Two (2) grams of one of the cream formulations of Example 7 for each kgof pig weight is distributed over the clipped skin area by gentleinunction with a glass stirring rod or stainless-steel spatula. Thecream formulation is applied evenly with a thin, uniform film beginningat the scapular region and moving caudally over the test site. The widthof the test site area is bilaterally divided by the spine. Eighteen pigsare divided into 3 groups of six pigs (3 males and 3 females) and thepigs of each group were dosed with one of the formulations 4, 5, or 6.Blood is sampled from the anterior vena cava through the thoracic inletor other suitable vein pre-dose (time=0) and at 1, 2, 4, 8 and 24 hourspost dose administration. The results are shown graphically in FIG. 13 .

As shown in FIG. 13 , pigs dosed with Formulation 7 of the prior artshow a rapid spike to a Cmax value of 6.6 ng/mL at 1 hour after the14^(th) consecutive daily dose. In contrast, pigs dosed with Formulation6 of the invention containing the phosphate ester surfactant CrodafosCES show little or no spike to Cmax.

The results show in the graph of FIG. 13 , that the steady state PKprofile data after 14 days of once daily dosing for the formulation ofthe invention lacks a significant spike to Cmax and has a low Cmax,while maintaining AUC, in contrast to PK data for the prior artformulation or a formulation using a phosphate ester surfactant that wasnot Crodafos CES. These results are especially surprising in view of thefact that the prior art (Bolle) teaches that Cmax and AUC are similarfor topical preparations containing roflumilast, irrespective of thecomposition of the topical formulation.

EXAMPLE 9—TESTING FOR MULTIPLE DOSE PHARMACOKINETICS COMPARED TO PRIORART

A fourth formulation of the invention is shown in Table 3, hereafterreferred to as Formulation 9, was made by combining the aboveconstituents and adding diethylene glycol monoethyl ether, as well asother ingredients to create a complete formulation. This formulation wasbuffered with NaOH to obtain a pH of 5.5. The qualitative andquantitative composition of Formulation 9 varies only in the amount ofroflumilast added to the cream. As a fraction of 1% roflumilast isadded, a fraction of 1% of water is removed from the cream.

TABLE 3 Formulation 9 Roflumilast 0.15, 0.3, 0.5 or 1.0% w/w Petrolatum,USP  10.0% w/w Isopropyl Palmitate, NF  5.0% w/w Crodafos CES  10.0% w/wcetostearyl alcohol (6-8% w/w) dicetyl phosphate (1-2% w/w) ceteth-10phosphate (1-2% w/w) Diethylene Glycol Monoethyl Ether, NF  25.0% w/wHexylene Glycol, NF  2.0% w/w Methylparaben, NF  0.20% w/wPropylparaben, NF 0.050% w/w 1N NaOH, NF q.s. ad pH 5.5 Purified Water,USP q.s. ad 100%

Male and female swine (Gottingen Minipig® breed) were ordered to weigh 8to 12 kg at arrival. On the day prior to administration of a topicalcream containing roflumilast, the hair was clipped from the back of eachanimal. The pigs were sedated for the shaving procedure. Care was takento avoid abrading the skin.

Two (2) grams of the cream Formulation 7 having varying concentrationsof roflumilast, for each kg of pig weight was distributed over theclipped skin area by gentle inunction with a glass stirring rod orstainless-steel spatula. The cream was applied evenly with a thin,uniform film beginning at the scapular region and moving caudally overthe test site. The width of the test site area was bilaterally dividedby the spine. Twenty pigs (10 males and 10 females) were dosed with 1%roflumilast cream, twelve pigs (6 males and 6 females) were dosed with0.5% roflumilast cream, and twelve pigs (6 males and 6 females) weredosed with 0.15% roflumilast cream, each dosed daily for 28 days. Sixpigs (3 males and 3 females) were each dosed daily with 0.3% roflumilastcream (formulation 7) for 14-days. Blood was sampled from a suitablevein pre-dose (time=0), and at times 1, 2, 4, 8 and 24 hours post doseadministration on day 1 and day 28 (or day 14 for 0.3% roflumilast) ofdosing. The results are shown graphically in FIG. 14 (0.15% roflumilastcream), in FIG. 15 (0.3% roflumilast), in FIG. 16 (0.5% roflumilastcream), and in FIG. 17 (1.0% roflumilast cream) and in tabular form inTable 4.

As shown in each of FIGS. 14 to 17 , the gradual ascent to Cmax isevident from the day 1 pharmacokinetic profile. What is most strikingand surprising about the data shown in FIGS. 14 to 17 is the very flatand prolonged plateau in blood levels of the drug following Cmax in theday 28 or day 14 (0.3% roflumilast cream) pharmacokinetic profile, afterreaching steady state drug delivery.

TABLE 4 Trough (T = 0) Peak or Cmax Topical Product Dosed (ng/ml)(ng/ml) 0.15% Roflumilast Cream 4.5 (females) 4.9 (females) (FIG.14--Steady State Day 28) 5.0 (males) 5.0 (males) 0.3% Roflumilast Cream3.7 (females) 4.5 (females) (FIG. 15--Steady State Day 14) 6.6 (males)6.6 (males) 0.5% Roflumilast Cream 8.5 (females) 10.7 (females) (FIG.16--Steady State Day 28) 6.7 (males) 8.2 (males) 1% Roflumilast Cream16.3 (females) 16.3 (females) (FIG. 17--Steady State Day 28) 8.4 (males)10.0 (males)

Likewise, the data of Table 4 show an extremely small variation in bloodconcentration between the trough and peak (Cmax) following theattainment of steady state for each of the four concentrations ofroflumilast when the formulation of the present invention is topicallyapplied.

EXAMPLE 10—CLINICAL STUDY IN SUBJECTS WITH PLAQUE PSORIASIS Study Design

ARQ-151 is a topical cream which contains roflumilast. This phase 1/2aclinical trial enrolled two cohorts: Cohort 1 evaluated a singleadministration of ARQ-151 cream 0.5% and Cohort 2 evaluated ARQ-151cream 0.5% or 0.15% applied once daily for 28 days. In Cohort 1,subjects applied ARQ-151 cream 0.5% to 25 cm 2 of psoriatic plaque(s).Subjects were screened (Visit 1), returned to the clinic for treatment(Visit 2) and PK blood draws, had a follow-up visit at 24 hours afterthe baseline visit for a PK blood draw (Visit 3), and received afollow-up telephone contact for safety evaluation 7 days after Visit 3.Subjects enrolled in Cohort 1 could be enrolled in Cohort 2 if they meteligibility criteria; subjects from Cohort 1 who rolled into Cohort 2had all of their plaque(s) treated in Cohort 2 up to 5% body surfacearea (BSA).

Cohort 2 used a parallel-group, double-blind, vehicle-controlled studydesign. Subjects were randomly assigned in a 1:1:1 ratio to ARQ-151cream 0.5%, ARQ-151 cream 0.15%, or a matched vehicle, which was appliedto all psoriatic plaques (except on the face, intertriginous areas,scalp, palms, and soles) up to an application area of 5% BSA. Subjectsin Cohort 2 had screening and baseline visits, follow-up visits at weeks1, 2, 3, and 4, an additional visit at day 29 for a finalpharmacokinetic sample collection, and a follow-up telephone call forsafety evaluation at week 5.

Cohort 1 received open-label treatment, without assignment or blinding.Assignment to treatment arm in Cohort 2 was performed using acomputer-generated randomization list. Randomization was generated usingSAS by an unblinded Premier Research statistician who was otherwise notinvolved in study conduct. The block size was 3; 72 total blocks wereused. Everyone was blinded to treatment.

This study was conducted in accordance with the principles of theDeclaration of Helsinki and Good Clinical Practice. The protocol wasapproved by Research Review Board, Inc., Richmond Hill, ON, Canada forall sites. All subjects provided written informed consent prior toinitiation of any study-specific procedures. This trial was registeredunder ClinicalTrials.gov #NCT03392168.

Manufacture of ARQ-151 Cream (Formulation 9)

A target amount of 480 grams sterile water for irrigation-USP wasaccurately weighed into a 1000 ml glass beaker and 20 grams of sodiumhydroxide pellets-NF was added and mixed using a stir bar until completedissolution. This solution was set aside and labeled 1 N SodiumHydroxide.

Target weights pf 1,000 grams white petrolatum-USP, 500 grams isopropylpalmitate-NF, and 1,000 grams of phosphate-ester self-emulsifying wax(CRODAFOS™ CES) were weighed into a 4 L glass beaker and heated on a hotplate to 75° C. to 80° C. while mixing with a propeller mixer. Themixture was labeled Oil Phase and was maintained at 75° C. to 80° C.

To the Main Manufacturing Vessel (a 20 L stainless steel vessel) atarget weight of 4,225 grams of sterile water for irrigation-USP and atarget weight 300 grams 1N sodium hydroxide were added and heated on ahot plate to 75° C. to 80° C. This was recorded as the Aqueous Phase andwas maintained at 75° C. to 80° C.

Target weights of 2,400 grams of Transcutol P-NF, 200 grams of hexyleneglycol-NF, 20.0 grams of methylparaben-NF, and 5.0 grams ofpropylparaben NF were accurately weighed into a 7 L stainless steelbeaker and propeller mixed until a clear homogeneous solution wasobtained. Sufficient potency corrected roflumilast was added to thissolution to obtain either a 0.15% roflumilast cream or a 0.5%roflumilast cream and this was labeled the API Phase.

The Oil Phase that was maintained at 75° C. to 80° C. was slowly addedto the Aqueous Phase maintained at 75° C. to 80° C. in the MainManufacturing Vessel with homogenizer mixing until a smooth, homogeneouscream was obtained. Using propeller mixing, the cream was cooled to 45°C. to 50° C. The API Phase was slowly added to the cream in the mainmanufacturing vessel and was mixed with the homogenizer. The pH of thefinished cream was measured and adjusted to within the pH range of 5.1to 5.9 using 1 N Sodium Hydroxide or Diluted Hydrochloric Acid, 10%(w/v)-NF. After bulk product release, the cream was filled into aluminum¾×3¾ #16 sealed white tubes and the tubes crimped to provide the primarycontainer closure system.

Patients

To be eligible for enrollment in Cohort 1, subjects had to be ≥18 yearsof age with ≥25 cm² of chronic plaque psoriasis. To be eligible forenrollment in Cohort 2, subjects also had to have chronic plaquepsoriasis of ≥6 months duration covering 0.5% to 5.0% of total BSAexcluding the face, scalp, intertriginous areas, palms, and soles.Subjects needed to have at least 1 (and up to 3) target plaque(s)≥9 cm²in size with a Target Plaque Severity Score (TPSS)≥4. Target plaquescould be located anywhere on the body (excluding the face, scalp,intertriginous areas, palms, and soles), including the knees and elbows.Key exclusion criteria included: non-plaque forms of psoriasis,drug-induced psoriasis, skin conditions that would interfere with studyassessments, known allergies to excipients in ARQ-151 cream,hypersensitivity to PDE-4 inhibitors, inability to discontinue use ofstrong P-450 cytochrome inducers or P-450 cytochrome inhibitors,inability to refrain from use of a tanning bed, inability to discontinuesystemic or topical therapies for the treatment of psoriasis, activeinfection requiring oral or intravenous antibiotics, antifungal, orantiviral agents within 7 days of baseline, or current or history ofcancer within 5 years except for fully excised skin basal cellcarcinoma, cutaneous squamous cell carcinoma, or cervical carcinoma.

Treatments and Application

Formulation 9, also known as ARQ-151 cream, contained 0.5% or 0.15%roflumilast. Vehicle contained all ingredients in the ARQ-151 creamexcept roflumilast. In Cohort 1, ARQ-151 cream 0.5% was applied in theclinic to 25 cm² of psoriatic plaque(s). In Cohort 2, all psoriaticlesions up to 5% BSA (except for those on the face, scalp,intertriginous areas, palms, and soles) were treated at home by subjectsonce daily for 4 weeks. Subjects were instructed by study staff onproper dosing and administration of ARQ-151 cream and vehicle.

Study Assessments

Assessments of efficacy (Cohort 2 only), pharmacokinetics (bothcohorts), and safety (both cohorts) were conducted. The primary andsecondary efficacy endpoints were calculated based on the product ofTarget Plaque Severity Score (TPSS) and Target Plaque Area (TPA). TheTPSS was determined for each target plaque on each subject as the sum oferythema, thickness, and scaling scores, each rated on a scale of 0(none) to 4 (very severe) and was identical to the severity scoring usedin the PASI. TPA (cm²) was determined by multiplying the longestdiameter (cm) of the target plaque by the widest perpendicular diameter(cm). Thus, the product of TPSS×TPA was roughly analogous to a PASI forthe treated plaque. TPSS and TPA assessments were conducted atscreening, baseline, and weeks 1, 2, 3, and 4.

Pharmacokinetic profiles for roflumilast and its active metaboliteroflumilast N-oxide12 were determined from plasma. Blood samples forpharmacokinetic analyses were collected on day 1 at 1, 2, 4, and 6 hoursafter ARQ-151 application. On day 28, samples were collected beforedosing (trough level) and at 1, 2, 4, 6, and 24 hours after application.

Safety endpoints included the type and incidence of treatment-emergentadverse events (TEAEs) and serious adverse events (SAEs); applicationsite reactions; and changes in physical examinations, vital signs,electrocardiograms, and clinical laboratory parameters. Safety wasassessed at all study visits and at telephone follow-up. Skin irritationwas assessed on days 1 and 2 for Cohort 1 and at baseline and visits 3(week 1), 4 (week 2), 5 (week 3), and 6 (week 4) for Cohort 2. Skinirritation was evaluated using a scale developed by Berger and Bowmanranging from 0 (no evidence of irritation) to 7 (strong reactionspreading beyond application site). Additionally, other clinical signsof irritation were scored on an ‘A’ (slight glazed appearance) to ‘F’(small petechial erosions and/or scabs) scale. An additional safetyendpoint was the results from the Depressive SymptomatologyQuestionnaire, 14 which was administered at screening, week 2, and week4. The questionnaire is a 16-item inventory of depressive symptoms, witheach item scored on a range of 0 to 3. Depression severity is based onscore category, where total score≤5 represents no depression; 6-10represents mild depression; 11-15 represents moderate depression; 16-20represents severe depression; and ≥21 represents very severe depression.

Statistical Considerations

For Cohort 2, a sample size of 24 subjects per arm (72 total subjects)was estimated to provide 80% power to detect a difference of 23% in themean percentage change from baseline in the primary endpoint between theARQ-151 cream and matching vehicle arm. This estimation was based on a1-way analysis of variance at the α=0.025 significance level. Toaccommodate a 16% drop-out rate, the total sample size was increased to84 subjects.

TEAEs were coded using the Medical Dictionary for Regulatory Activities(MedDRA) version 20.1, and severity was graded on a 5-point scale ofGrade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4(life-threatening consequences), or Grade 5 (death related to AE).

Pharmacokinetic parameters were calculated using the plasmaconcentration values of roflumilast and roflumilast N-oxide (ng/mL) ateach nominal time point with Phoenix WinNonlin (v8.0) using standardnoncompartmental analysis. The area under the concentration time curve(AUC) was estimated using the linear trapezoidal interpolation method.The maximum plasma concentration (Cmax) and time to reach maximumconcentration (Tmax) were based on direct assessment. Sampleconcentration values reported to be below the limit of quantification(BLQ; <0.100 ng/mL) were ignored.

The primary efficacy endpoint was the difference in mean percentagechange from baseline at week 4 in the product of TPSS×TPA between eachdose of ARQ-151 cream and vehicle control. The primary efficacy endpointwas analyzed using a mixed model for repeated measures with centerwithin country, treatment, study visit, and treatment-by-study-visitinteraction as fixed effects and baseline TPSS×TPA score as a covariate.Mean differences between visit value and baseline were calculated foreach treatment. Mean percentage change from baseline for each ARQ-151dose and corresponding vehicle were compared using an unstructuredcovariance structure unless the model did not converge; in that case theappropriate covariance structure was investigated. The Bonferroni methodwas used to control for multiplicity, where the significance level foreach of pairwise comparisons of active vs placebo was at α=0.025.

Secondary efficacy endpoints included the difference in mean percentagechange from baseline at weeks 1, 2, and 3 in composite TPSS×TPA score,TPSS, and TPA between each dose of ARQ-151 cream and vehicle control.Statistical analyses of secondary efficacy endpoints were the same asthose used for the primary endpoint, except no adjustments formultiplicity were used and all analyses were conducted at the α=0.05level.

In a post hoc analysis, the percentage of subjects with 75% and 90%improvement from baseline in TPSS×TPA (75% responders and 90%responders) at each study visit through week 4 were also evaluated.

Safety analyses were conducted with the safety population, whichcomprised all subjects who received at least 1 dose of study drug andwere based on treatment received. Pharmacokinetic analyses wereconducted with the pharmacokinetic population, which included allsubjects who consented for sampling and received active drug withsufficient plasma concentrations of roflumilast to define a profile.Efficacy analyses were conducted with the modified intent-to-treatpopulation, which was composed of all subjects in Cohort 2 who received≥1 dose of study drug and had ≥1 post-baseline efficacy evaluation.

No imputation was used for missing data. Data processing, tabulation ofdescriptive statistics, calculation of inferential statistics, andgraphical representations (except for PK parameter estimation) wereperformed primarily using SAS (release 9.4). All PK parameterestimations were performed using WinNonlin® version 6.4 or later.

Results Patients

Subjects were recruited from 7 study sites in Canada and from 1 site inthe US between Dec. 5, 2017 (first patient enrolled) and May 2, 2018(last follow-up visit). Eight subjects enrolled in Cohort 1, and 89subjects enrolled in Cohort 2, including subjects randomly assigned toARQ-151 cream 0.5% (N=30), ARQ-151 cream 0.15% (N=28), and vehicle(N=31). All subjects in Cohort 1 received treatment and completed thestudy, and 6 also participated in Cohort 2. Four subjects in Cohort 2discontinued early from the study because of loss to follow-up (n=3) orother reasons (n=1). There were no discontinuations due to AEs. Thesafety populations comprised all 8 subjects in Cohort 1 and all 89subjects in Cohort 2. The PK population included 20 subjects whoreceived Formulation 7 (ARQ-151 cream) 0.5% and 22 subjects who receivedFormulation 7 (ARQ-151 cream) 0.15%. The efficacy population comprisedall subjects in Cohort 2.

The mean age (standard deviation [SD]) was 51.6 (16.9) years for Cohort1 and mean age ranged from 47.5 to 55.3 years across Cohort 2 treatmentarms (Table 5). Most subjects were white. The average BSA of involvementwas ˜2% in all treatment groups. Of the 89 subjects enrolled in Cohort2, 35 (39.3%) had target plaques located on the knees, elbows, or both.

TABLE 5 Subject Characteristics (Safety Population) Cohort 1 Cohort 2ARQ-151 ARQ-151 ARQ-151 0.5% 0.5% 0.15% Vehicle (N = 8) (N = 30) (N =28) (N = 31) Age, mean 51.6 (16.9) 49.9 (15.9) 55.3 (13.2) 47.5 (14.7)years (SD) Sex, n (%) Male 1 (12.5) 16 (53.3) 19 (67.9) 18 (58.1) Female7 (87.5) 14 (46.7) 9 (32.1) 13 (41.9) Race, n (%) White 8 (100) 25(83.3) 24 (85.7) 22 (71.0) Asian 0 2 (6.7) 2 (7.1) 8 (25.8)Black/African 0 2 (6.7) 2 (7.1) 0 American Other 0 1 (3.3) 0 1 (3.2)Psoriasis- NC 3.06 (1.39) 2.73 (1.32) 2.21 (1.05) affected BSA, mean m²(SD) BSA, body surface area; NC, not collected; SD, standard deviation.

Efficacy Results

The primary efficacy endpoint was met: the mean percentage change frombaseline in TPSS×TPA at week 4 was significantly different from vehiclefor ARQ-151 cream 0.5% (P=0.0007) and ARQ-151 cream 0.15% (P=0.0011)(FIG. 7A). For both concentrations of ARQ-151 cream, 66%-67% improvementfrom baseline was observed in the primary endpoint after 4 weeks oftreatment vs 38% for vehicle, based on least square (LS) mean percentagechange from baseline. Statistical separation from vehicle was reachedfor both drug product concentrations as early as week 2 of treatment,and the difference between drug product and vehicle continued toincrease through week 4. Both ARQ-151 cream 0.5% and 0.15% showedsimilar efficacy in this primary endpoint throughout the study duration.

Secondary efficacy endpoints of change from baseline in TPSS (FIG. 7B)and change from baseline in TPA (FIG. 7C) were statisticallysignificantly different between ARQ-151 at both active concentrationsand vehicle after 4 weeks of treatment. For both active concentrationsof ARQ-151 vs vehicle, change from baseline in TPSS, but not TPA,reached statistical significance as early as 2 weeks.

Patients receiving ARQ-151 cream 0.5%, 0.15% and vehicle after 4 weeksof treatment were compared to baseline, along with their respectiveTPSS×TPA scores. Of note, the vehicle-treated subjects seemed to haveimprovement mainly in the appearance of scaling (predictable for anemollient cream). Both subjects receiving ARQ-151 cream 0.5% and 0.15%show examples of substantial improvement in the elbows or knees, whichcan be treatment-resistant areas of psoriasis. Indeed, 39.3% of subjectshad target plaques on the elbows and/or knees.

In a post hoc analysis, 75% responder rates (75% improvement frombaseline in TPSS×TPA) at week 4 were also evaluated. In the ARQ-151cream 0.5% group, 10 subjects (35.7%) achieved this level of improvement(P=0.0090), and in the ARQ-151 cream 0.15% group, 7 subjects (25.9%)were 75% responders (P=0.0700). There were two 75% responders (6.4%) inthe vehicle group. In this same analysis, 90% responder rates at week 4were also evaluated. In the ARQ-151 cream 0.5% group, 4 subjects (14.3%)achieved this level of improvement, and in the ARQ-151 cream 0.15%group, 3 subjects (11.1%) were 90% responders; however, none of the 90%responder rates was statistically significant. There was one 90%responder (3.2%) in the vehicle group.

Pharmacokinetic Results

In Cohort 1, limited evidence of systemic plasma exposure to roflumilastor roflumilast N-oxide was observed after a single topicaladministration of ARQ-151 0.5% to 25 cm² of psoriatic plaques (data notshown). In Cohort 2, systemic plasma exposure to roflumilast androflumilast N-oxide was observed following single or multipleapplications of Formulation 7 (ARQ-151) to psoriatic plaques covering0.5% to 5% BSA (Table 8, FIG. 8A for 0.5% Formulation 7, ARQ-151 creamand FIG. 8B for 0.15% Formulation 7, ARQ-151 cream). On day 1,roflumilast but not roflumilast N-oxide exposure appeared to increase ina dose-dependent manner. At day 28, the plasma concentration vs timeprofiles were relatively flat (very small peak to trough differences)suggesting that roflumilast and roflumilast N-oxide exposure achievedsteady state and appeared to increase in a dose-dependent manner. Theratio of N-oxide to roflumilast after topical administration ranged from4.7 to 5.9, compared with 12 after oral administration of roflumilast,the latter being higher due to increased contribution from first passmetabolism.

As shown in FIGS. 19A and 19B, when roflumilast is formulated in a creamcontaining the phosphate ester surfactant Crodafos CES, the gradualascent to Cmax is evident in the single dose and steady-statepharmacokinetic profile. As shown in FIGS. 19A and 19B, there is a veryflat and prolonged plateau in blood levels of the drug following Cmaxfor the 24-hours following the first application of 0.15% or 0.5%Formulation 9 (ARQ-151 cream) in human subjects. The pharmacokineticprofile of roflumilast after dosing the skin with Formulation 9 has thesame low rise to Cmax shape when applied to humans or pigs.

TABLE 6 Pharmacokinetic Parameters (Pharmacokinetic Population; Cohort2) ARQ-151 ARQ-151 0.5% 0.15% Day 1 Roflumilast AUC_(0-last), mean h ×ng/mL (SD) [n] 4.37 (5.84) [10] 2.34 (2.56) [7] C_(max), mean ng/mL (SD)[n] 1.38 (2.26) [10] 0.578 (0.468) [7] T_(max), mean h {minimum,maximum} [n] 3.20 {1.00, 6.00} [10] 3.71 {1.00, 6.00} [7] RoflumilastN-oxide AUC_(0-last), mean h × ng/ml (SD) [n] 2.61 (2.13) [4] 3.18(2.54) [2] C_(max), mean ng/ml (SD) [n] 0.965 (0.858) [4] 1.07 (0.950)[2] T_(max), mean h [minimum, maximum] [n] 6.00 {6.00, 6.00} [4] 6.00{6.00, 6.00} [2] Day 28 Roflumilast AUC_(0-last), mean h × ng/ml (SD)[n] 29.2 (19.9) [20] 24.4 (22.8) [21] C_(max), mean ng/ml (SD) [n] 1.48(0.978) [20] 1.30 (1.06) [21] T_(max), mean h [minimum, maximum] [n]3.70 {0.00, 24.0} [20] 4.95 {0.00, 24.0} [21] Roflumilast N-oxideAUC_(0-last), mean h × ng/ml (SD) [n] 172 (116) [20] 127 (119) [22]C_(max), mean ng/mL (SD) [n] 8.41 (5.54) [20] 6.11 (5.53) [22] T_(max),mean h [minimum, maximum] [n] 8.25 {0.00, 24.0} [20] 8.59 {0.00, 24.0}[22] AUC_(0-last), area under the concentration time curve until thelast measurable time point; C_(max), maximum plasma concentration;T_(max), time to maximum plasma concentration.

Safety Results

In Cohort 1, only 1 subject reported a TEAE, which was consideredunrelated to treatment (Table 7). In Cohort 2, the percent of TEAEs inthe 0.15% group was lower than in the 0.5% or vehicle groups (7.1% vs23.3% and 25.8%, respectively, for treatment-related TEAEs; and 25% vs40% and 35.5%, respectively, for all TEAEs) (Table 7); all were mild ormoderate in severity. No SAE was reported in this study, and no subjectdiscontinued from the study because of a TEAE. All treatment-relatedTEAEs were associated with the application site, accounting for 17events. Application site TEAEs were generally mild in severity andnumber (16 events were mild and 1 event was moderate) and showed noconsistent differences between drug product and vehicle. No changes inphysical examinations, vital signs, electrocardiograms, or clinicallaboratory parameters were considered clinically meaningful. There wereno clinically significant differences in weight changes betweentreatment groups. One subject in the 0.5% treatment group reported asingle episode of nausea of moderate severity, but no further episodesin the remaining 3 weeks of the study. No subjects reported vomiting ordiarrhea. No signs of skin irritation (dermal reactions) were noted inCohort 1. For Cohort 2, mean (SD) dermal reaction scores at baseline forARQ-151 cream 0.5%, 0.15%, and vehicle were 0.2 (0.5), 0.0 (0.2), and0.2 (0.4), respectively, and at week 4 were 0.1 (0.5), 0.0 (0.0), and0.1 (0.4).

TABLE 7 Summary of Safety (Safety Population) Cohort 1 Cohort 2 ARQ-151ARQ-151 ARQ-151 0.5% 0.5% 0.15% Vehicle (N = 8) (N = 30) (N = 28) (N =31) Subjects with, n (%): ≥1 TEAE 1 (12.5) 12 (40.0) 7 (25.0) 11 (35.5)Treatment-related TEAE 0 7 (23.3) 2 (7.1) 8 (25.8) TEAE leading to 0 0 00 discontinuation SAE 0 0 0 0 Maximum severity of TEAEs, n (%) Mild 0 7(23.3) 3 (10.7) 6 (19.4) Moderate 1 (12.5) 5 (16.7) 4 (14.3) 5 (16.1)Application site TEAEs, n (%) Erythema 0 4 (13.3) 1 (3.6) 4 (12.9) Pain0 2 (6.7) 1 (3.6) 5 (16.1) Edema 0 1 (3.3) 0 1 (3.2) Papules 0 1 (3.3) 01 (3.2) Pruritus 0 1 (3.3) 1 (3.6) 0 SAE, serious adverse event; TEAE,treatment-emergent adverse event.

Discussion

In this phase 1/2a clinical trial, Formulation 9 (ARQ-151 cream) 0.5%and 0.15% was well tolerated, safe, and effective for the treatment ofchronic plaque psoriasis. Formulation 9 (ARQ-151 cream) at both dosestested demonstrated strong efficacy as shown by statisticallysignificant reductions in plaque severity and size compared to vehicle.

Statistically significant efficacy of ARQ-151 (Formulation 9 containing0.15% or 0.5% roflumilast) as compared to vehicle in the primary studyendpoint was observed with both active doses as early as 2 weeks afterinitiation of treatment, and differences between ARQ-151 and vehiclecontinued to increase through the last visit at 4 weeks. LS meanTPSS×TPA values decreased 38% with vehicle over the course of the study;the preponderance of this effect occurred during week 1 of treatment,which was likely contributed to by apparently decreased scaling to theobserver's eye caused by the emollient cream. There was no difference inefficacy between ARQ-151 cream 0.5% and 0.15% in the primary endpoint(percentage change from baseline in TPSS×TPA) at week 4. However, the75% responder rates at week 4 suggested the 0.5% cream was somewhat moreefficacious (35.7%; P=0.0090 vs vehicle) than the 0.15% concentration(25.9%; P=0.0700). With both active drug concentrations after 4 weeks ofdosing, TPSS×TPA values were already reduced by 66%-67% from baselinebased on LS means. However, TPSS×TPA did not plateau in subjects treatedwith ARQ-151, suggesting that a longer duration of treatment mightprovide even greater efficacy.

The TPSS×TPA endpoint was chosen to be analogous to whole-body PsoriasisArea and Severity Index (PASI) measurements. Both use the same plaqueseverity scale, which was applied to 1-3 target lesions in the currentstudy vs the entire body with PASI. The TPA ‘area’ function is differentfrom the area of plaque involvement assessment in PASI, but we wouldpropose that the product of TPSS×TPA provides an analogous assessment of‘target plaque(s)’ to PASI for the entire body. Based on thisassumption, the efficacy of topical ARQ-151 after 4 weeks of dosing(with 35.7% of subjects reaching 75% improvement for the 0.5% cream) maybe comparable to that of the class 1 steroid betamethasone dipropionate0.064% (32.7% PASI 75 response rate after 4 weeks of dosing) in thephase 3 studies of Taclonex®.

The safety profile of Formulation 9 (ARQ-151 cream) at both 0.5% and0.15% was similar to vehicle, which is explained, at least in part, bythe pharmacokinetic findings. When administered orally for COPD,roflumilast may be associated with gastrointestinal side effects(diarrhea, nausea, vomiting), psychiatric disturbances (insomnia,anxiety, depression, suicidal thoughts or other mood changes), weightloss in a minority of patients, and headache. Typically, clinicaldevelopment of PDE-4 inhibitors for oral use has been limited bygastrointestinal effects such as nausea and vomiting. Indeed, nausea,vomiting, psychiatric disturbances, and weight loss are believed to bemediated at the level of the brain. In contrast to oral administration,topical administration of roflumilast in our study was associated with aslow ascent to maximum plasma concentrations over multiple days, and aflat exposure to roflumilast and its active metabolite roflumilastN-oxide throughout the dosing period (i.e. C_(max)˜C_(min) across dosinginterval). The lack of nausea and vomiting seen in the present studycould possibly be attributed the lack of ‘peak to trough’ C_(max)variation; lower C_(max) values than observed following oraladministration; or bypassing of the gastrointestinal tract with topicaladministration. The absence of psychiatric disturbances and weight lossseen in our studies may also be explained by the markedly different PKof topical vs oral administration. PDE-4 inhibition represents avalidated mechanism of action for oral psoriasis therapy (Otezla), but anew mechanism of action for topical psoriasis therapy. Patients withmild to moderate disease represent the majority of the psoriasispopulation. This patient population has not benefited from the recentintroduction of biologic therapies, which are used in patients with moresevere disease. However, it is not surprising that roflumilast is aneffective modality for the treatment of psoriasis. Roflumilast is ahighly potent PDE-4 inhibitor, exhibiting half maximal inhibitoryconcentration (IC₅₀) values of both roflumilast and roflumilast N-oxidefor the different PDE-4 isoforms and subtypes at subnanomolar potency.Rolumilast is 50- to 300-fold more potent than either apremilast orcrisaborole against the different PDE-4 isoforms and subtypes. The oraldose of roflumilast, at only 0.5 mg per day, is reflective of thisextremely high potency.

Further modifications, uses, and applications of the invention describedherein will be apparent to those skilled in the art. It is intended thatsuch modifications be encompassed in the following claims.

EXAMPLE 11—PREPARING A FOAM FORMULATION

A fifth formulation of the invention is shown in Table 8, hereinafterreferred to as Formulation 10. Formulation 10 is a foam concentratewhich can be mixed with a propellant to produce a foam. Sixty four gramsof the foam concentrate was blended with 8-10 grams of AP-70 propellantto make a foam.

TABLE 8 Formulation 10 Roflumilast 0.15, 0.3, 0.5 or 1.0% w/wPetrolatum, USP  5.0% w/w Isopropyl Palmitate, NF  2.5% w/w Crodafos CES   2% w/w cetostearyl alcohol (1.2-1.6% w/w) dicetyl phosphate (0.2-0.5%w/w) ceteth-10 phosphate (0.2-0.5% w/w) Diethylene Glycol MonoethylEther, NF  25.0% w/w Hexylene Glycol, NF  2.0% w/w Methylparaben, NF 0.20% w/w Propylparaben, NF 0.050% w/w 1N NaOH, NF q.s. ad pH 5.5Purified Water, USP q.s. ad 100%

EXAMPLE 12—COMPARISON OF ADVERSE EVENT PROFILES OF DALIRESP AND TOPICALFORMULATIONS

Treatment of 4,438 patients with once daily DALIRESP® 500 mcg tabletswas associated with an increase in psychiatric adverse reactions andweight loss. In 8 controlled clinical trials 5.9% (263) of patientstreated with DALIRESP® 500 mcg daily reported psychiatric adversereactions compared to 3.3% (137) treated with placebo. The most commonlyreported psychiatric adverse reactions were insomnia, anxiety, anddepression which were reported at higher rates in those treated withDALIRESP® 500 mcg daily (2.4%, 1.4%, and 1.2% for DALIRESP® versus 1.0%,0.9%, and 0.9% for placebo, respectively). Instances of suicidalideation and behavior, including completed suicide, have been observedin clinical trials. Three patients experienced suicide-related adversereactions (one completed suicide and two suicide attempts) whilereceiving DALIRESP® compared to one patient (suicidal ideation) whoreceived placebo. Cases of suicidal ideation and behavior, includingcompleted suicide, have been observed in the post-marketing setting inpatients with or without a history of depression. Weight loss was acommon adverse reaction in DALIRESP® clinical trials and was reported in7.5% (331) of patients treated with DALIRESP® 500 mcg once dailycompared to 2.1% (89) treated with placebo [see DALIRESP® 500 mcgpackage insert Adverse Reactions (6.1)]. In addition to being reportedas adverse reactions, weight was prospectively assessed in twoplacebo-controlled clinical trials of one-year duration. In thesestudies, 20% of patients receiving roflumilast experienced moderateweight loss (defined as between 5-10% of body weight) compared to 7% ofpatients who received placebo. In addition, 7% of patients who receivedroflumilast compared to 2% of patients receiving placebo experiencedsevere (>10% body weight) weight loss. During follow-up after treatmentdiscontinuation, the majority of patients with weight loss regained someof the weight they had lost while receiving DALIRESP®. (Section 5.2 and5.3 of the Daliresp package insert)

In contrast to the psychiatric adverse reactions and weight lossassociated with orally administered roflumilast (Daliresp® 500 μgtablets), no significant safety concerns or signals have been identifiedduring the completed or ongoing clinical studies of roflumilast cream orroflumilast foam. It is estimated that about 2,412 clinical trialsubjects have been exposed to at least one dose of topical roflumilastcream or roflumilast foam. While adverse events associated with marketedoral roflumilast (Daliresp® 500 μg tablets), such as depression, weightloss and gastrointestinal adverse events, were assessed with regard totopical roflumilast cream and roflumilast foam studies, the side effectsassociated with oral administration of roflumilast have not beenobserved in roflumilast cream and roflumilast foam clinical studies. Thepharmacokinetic profile of topical roflumilast appears to be distinctfrom that of oral roflumilast likely due to the lack of ‘peak to trough’Cmax variation, lower Cmax values than observed following oraladministration, and/or bypassing of the gastrointestinal tract withtopical administration.

1. A topical roflumilast pharmaceutical composition having a roflumilastabsorption profile that produces in a patient following administration,a flattened plasma concentration time curve and a reduced Cmax relativeto oral administration of roflumilast in an oral composition marketedunder the trademark DALIRESP®.
 2. The composition of claim 1, whereinsaid topical composition is an emulsion comprising: (i) roflumilast,wherein the roflumilast is in an amount of 0.05-1.0% w/w; (ii) water;(iii) a hydrophobic component; (iv) a solvent; and (v) a surfactant. 3.The composition of claim 2, wherein said solvent comprises diethyleneglycol monoethyl ether.
 4. The composition of claim 2, wherein thesurfactant comprises a blend of ceteraryl alcohol, dicetyl phosphate,and ceteth-10 phosphate.
 5. The composition of claim 3, wherein thesurfactant comprises a blend of ceteraryl alcohol, dicetyl phosphate,and ceteth-10 phosphate.
 6. The composition of claim 2, wherein thehydrophobic component comprises petrolatum.
 7. The composition of claim3, wherein the hydrophobic component comprises petrolatum.
 8. Thecomposition of claim 5, wherein the hydrophobic component comprisespetrolatum.
 9. A topical roflumilast pharmaceutical composition having aroflumilast absorption profile that produces in a patient followingadministration a plasma concentration time curve having a delayed Tmaxrelative to oral administration of an oral composition marketed underthe trademark DALIRESP®.
 10. The composition of claim 9, wherein saidtopical composition is an emulsion comprising: (i) roflumilast, whereinthe roflumilast is in an amount of 0.05-1.0% w/w; (ii) water; (iii) ahydrophobic component; (iv) a solvent; and (v) a surfactant.
 11. Thecomposition of claim 10, wherein said solvent comprises diethyleneglycol monoethyl ether.
 12. The composition of claim 10, wherein thesurfactant comprises a blend of ceteraryl alcohol, dicetyl phosphate,and ceteth-10 phosphate.
 13. The composition of claim 11, wherein thesurfactant comprises a blend of ceteraryl alcohol, dicetyl phosphate,and ceteth-10 phosphate.
 14. The composition of claim 10, wherein thehydrophobic component comprises petrolatum.
 15. The composition of claim11, wherein the hydrophobic component comprises petrolatum.
 16. Thecomposition of claim 13, wherein the hydrophobic component comprisespetrolatum.
 17. The composition of claim 10, wherein said Tmax isbetween about 3 and 9 hours.
 18. A topical roflumilast pharmaceuticalcomposition having a roflumilast absorption profile that produces in apatient following administration a plasma concentration time curvehaving a higher area under the curve (AUC) relative to oraladministration of an oral composition marketed under the trademarkDALIRESP®.
 19. The composition of claim 18, wherein said topicalcomposition is an emulsion comprising: (i) roflumilast, wherein theroflumilast is in an amount of 0.05-1.0% w/w; (ii) water; (iii) ahydrophobic component; (iv) a solvent; and (v) a surfactant.
 20. Thecomposition of claim 19, wherein said solvent comprises diethyleneglycol monoethyl ether.
 21. The composition of claim 19, wherein thesurfactant comprises a blend of ceteraryl alcohol, dicetyl phosphate,and ceteth-10 phosphate.
 22. The composition of claim 20, wherein thesurfactant comprises a blend of ceteraryl alcohol, dicetyl phosphate,and ceteth-10 phosphate.
 23. The composition of claim 19, wherein thehydrophobic component comprises petrolatum.
 24. The composition of claim20, wherein the hydrophobic component comprises petrolatum.
 25. Thecomposition of claim 22, wherein the hydrophobic component comprisespetrolatum.